WO2000053754A1 - Compositions and methods for the treatment of tumor - Google Patents
Compositions and methods for the treatment of tumor Download PDFInfo
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- WO2000053754A1 WO2000053754A1 PCT/US2000/000277 US0000277W WO0053754A1 WO 2000053754 A1 WO2000053754 A1 WO 2000053754A1 US 0000277 W US0000277 W US 0000277W WO 0053754 A1 WO0053754 A1 WO 0053754A1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4702—Regulators; Modulating activity
- C07K14/4703—Inhibitors; Suppressors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2799/00—Uses of viruses
- C12N2799/02—Uses of viruses as vector
- C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
- C12N2799/026—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a baculovirus
Definitions
- Malignant tumors are the second leading cause of death in the United States, after heart disease (Boring et al , CA Cancel J Clin . 43 7 [1993])
- Cancer is characterized by an increase in the number of abnormal, or neoplastic cells derived from a normal tissue which proliferate to form a tumor mass, the invasion of adjacent tissues by these neoplastic tumor cells, and the generation of malignant cells which eventually spread via the blood or lymphatic system to regional lymph nodes and to distant sites (metastasis)
- a cell proliferates under conditions in which normal cells would not grow Cancer manifests itself in a wide variety of forms, characterized by different degrees of mvasiveness and aggressiveness Alteration of gene expression is intimately related to the uncontrolled cell growth and de-differentiation which are a common feature of all cancers
- the genomes of certain well studied tumors have been found to show decreased expression of recessive genes, usually referred to as tumor suppression genes, which would normally function to prevent malignant cell growth, and/or overexpression of certain dominant genes, such as oncogenes, that act to promote malignant giowth
- tumor suppression genes which would normally function to prevent malignant cell growth, and/or overexpression
- a well known mechanism of gene (e g oncogene) overexpression in cancer cells is gene amplification This is a process where in the chromosome of the ancestral cell multiple copies of a particular gene are produced The process involves unscheduled replication of the region of chromosome comprising the gene, followed by recombination of the replicated segments back into the chromosome (Alitalo et al , Adv Cancer Res , 47 235 281 [1986]) It is believed that the overexpression of the gene parallels gene amplification, ; e is proportionate to the number of copies made
- a recombinant humanized anti-ErbB2 (anti-HER2) monoclonal antibody (a humanized version of the murine anti-ErbB2 antibody 4D5, referred to as rhuMAb HER2 or HerceptinTM) has been clinically active in patients with ErbB2-overexpressing metastatic breast cancers that had received extensive prior anticancer therapy. (Baselga et al., J. Clin. Oncol.. 14:737-744 [1996]).
- anti-HER2 humanized anti-ErbB2
- the present invention concerns compositions and methods for the diagnosis and treatment of neoplastic cell growth and proliferation in mammals, including humans.
- the present invention is based on the identification of genes that are amplified in the genome of tumor cells. Such gene amplification is expected to be associated with the overexpression of the gene product and contribute to tumorigenesis. Accordingly, the proteins encoded by the amplified genes are believed to be useful targets for the diagnosis and/or treatment (including prevention) of certain cancers, and may act as predictors of the prognosis of tumor treatment.
- the present invention concerns an isolated antibody which binds to a polypeptide designated herein as a PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PRO ⁇ l 5, PR0531. PR0538, PR03664, PRO ⁇ l 8, PR0772, PRO703, PR0792 or PR0474 polypeptide.
- the isolated antibody specifically binds to a PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615. PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide.
- the antibody induces the death of a cell which expresses a PR0213, PRO1330, PR01449, PR0237, PR0324. PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664. PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide.
- the cell that expresses the PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PRO ⁇ l 8, PR0772, PRO703, PR0792 or PR0474 polypeptide is a tumor cell that overexpresses the polypeptide as compared to a normal cell of the same tissue type.
- the antibody is a monoclonal antibody, which preferably has non-human complementarity determining region (CDR) residues and human framework region (FR) residues. The antibody may be labeled and may be immobilized on a solid support.
- the antibody is an antibody fragment, a single-chain antibody, or a humanized antibody which binds, preferably specifically, to a PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide
- the invention concerns a composition of matter which comprises an antibody which binds, preferably specifically, to a PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide in admixture with a pharmaceutically acceptable carrier
- the composition of matter comprises a therapeutically effective amount of the antibody
- the composition comprises a further active ingredient, which may, for example, be a further antibody or a cytotoxic or chemotherapeutic agent
- the composition is sterile
- the invention concerns isolated nucleic acid molecules which encode anti- PR0213, anti PRO1330, ant ⁇ -PR01449, ant ⁇ -PR0237, ant ⁇ -PR0324, ant ⁇ -PR0351 , ant ⁇ -PR0362, ant ⁇ -PR0615, ant ⁇ -PR0531 , ant ⁇ -PR0538, ant ⁇ -PR03664, ant ⁇ -PR0618, ant ⁇ -PR0772, ant ⁇ -PRO703, ant ⁇ -PR0792 or anti- PR0474 antibodies, and vectors and recombinant host cells comprising such nucleic acid molecules
- the invention concerns a method for producing an ant ⁇ -PR0213, anti-
- the invention further concerns antagonists of a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PRO-531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide that inhibit one or more of the biological and/or lmmunological functions or activities of a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703 , PR0792 or PR0474 polypeptide
- the invention concerns an isolated nucleic acid molecule that hybridizes to a nucleic acid molecule encoding a PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR061 , PR0531 , PR0538, PR03664, PR0618 PR0772, PRO703, PR0792 or PR0474 polypeptide or the complement thereof
- the isolated nucleic acid molecule is preferably DNA, and hybridization preferably occurs under stringent hybridization and wash conditions
- Such nucleic acid molecules can act as antisense molecules of the amplified genes identified herein, which, in turn, can find use in the modulation of the transcription and/or translation of the respective amplified genes, or as antisense primers in amplification reactions
- sequences can be used as part of a ribozyme and/or a triple helix sequence which, in turn, may be used in regulation of the amplified genes
- the invention provides a method for determining the presence of
- the present invention concerns a method of diagnosing tumor in a mammal, comprising detecting the level of expression of a gene encoding a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide (a) in a test sample of tissue cells obtained from the mammal, and (b) in a control sample of known normal tissue cells of the same cell type, wherein a higher expression level in the test sample as compared to the control sample, is indicative of the presence of tumor m the mammal from which the test tissue cells were obtained
- the present invention concerns a method of diagnosing tumor in a mammal, comprising (a) contacting an ant ⁇ -PR0213, ant ⁇ -PRO1330, ant ⁇ -PR01449, ant ⁇ -PR0237, ant ⁇ -PR0324, anti- PR0351, ant ⁇ -PR0362, ant ⁇ -PR0615, ant ⁇ -PR0531 , ant ⁇ -PR0538, ant ⁇ -PR03664, ant ⁇ -PR0618, ant ⁇ -PR0772, ant ⁇ -PRO703, ant ⁇ -PR0792 or ant ⁇ -PR0474 antibody with a test sample of tissue cells obtained from the mammal, and (b) detecting the formation of a complex between the ant ⁇ -PR0213, ant ⁇ -PRO1330, ant ⁇ -PR01449, anti- PR0237, ant ⁇ -PR0324, ant ⁇ -PR0351 , ant ⁇ -PR0362, ant ⁇ -PR0615, ant ⁇ -PR
- the detection may be qualitative or quantitative, and may be performed in comparison with monitoring the complex formation in a control sample ot known normal tissue cells of the same cell type A larger quantity of complexes formed in the test sample indicates the presence of tumor in the mammal from which the test tissue cells were obtained
- the antibody preieiably cai nes a detectable label Complex formation can be monitored, for example, by light microscopy, flow cytometi) , fluo ⁇ metry, or other techniques known in the art
- test sample is usually obtained from an individual suspected to have neoplastic cell growth or proliferation (e g cancerous cells)
- the present invention concerns a cancer diagnostic kit comprising an ant ⁇ -PR0213, ant ⁇ -PRO1330, ant ⁇ -PR01449, ant ⁇ -PR0237, ant ⁇ -PR0324.
- a carrier e.g., a buffer
- the kit preferably contains instructions for using the antibody to detect the presence of a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PRO ⁇ l 5, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide in a sample suspected of containing the same.
- the invention concerns a method for inhibiting the growth of tumor cells comprising exposing tumor cells which express a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PRO ⁇ l 8, PR0772, PRO703, PR0792 or PR0474 polypeptide to an effective amount of an agent which inhibits a biological and/or immunological activity and/or the expression of a PR0213, PRO1330, PR01449, PR0237, PR0324.
- the agent preferably is an anti-PR0213, anti-PRO1330, anti-PR01449, anti-PR0237, anti- PR0324, anti-PR0351, anti-PR0362, anti-PR0615, anti-PR0531 , anti-PR0538, anti-PR03664, anti-PR0618, anti-PR0772, anti-PRO703, anti-PR0792 or anti-PR0474 antibody, a small organic and inorganic molecule, peptide, phosphopeptide, antisense or ribozyme molecule, or a triple helix molecule.
- the agent e.g., the anti-PR0213, anti-PRO1330, anti-PR01449, anti-PR0237, anti-PR0324, anti-PR0351, anti-PR0362, anti-PR0615, anti-PR0531, anti-PR0538, anti-PR03664, anti-PRO ⁇ l 8, anti-PR0772, anti-PRO703, anti-PR0792 or anti-PR0474 antibody, induces cell death.
- the tumor cells are further exposed to radiation treatment and/or a cytotoxic or chemotherapeutic agent.
- the invention concerns an article of manufacture, comprising: a container; a label on the container; and a composition comprising an active agent contained within the container; wherein the composition is effective for inhibiting the growth of tumor cells and the label on the container indicates that the composition can be used for treating conditions characterized by overexpression of a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PROG 18, PR0772, PRO703, PR0792 or PR0474 polypeptide as compared to a normal cell of the same tissue type.
- the active agent in the composition is an agent which inhibits an activity and/or the expression of a PR0213, PROl 330, PRO 1449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide.
- the active agent is an anti-PR0213, anti-PRO1330, anti- PR01449, anti-PR0237, anti-PR0324, anti-PR0351 , anti-PR0362, anti-PR0615, anti-PR0531 , anti-PR0538, anti-PR03664, anti-PRO ⁇ l 8, anti-PR0772, anti-PRO703. anti-PR0792 or anti-PR0474 antibody or an antisense oligonucleotide.
- the invention also provides a method for identifying a compound that inhibits an activity of a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664.
- PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide comprising contacting a candidate compound with a PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide under conditions and for a time sufficient to allow these two components to interact and determining whether a biological and/or immunological activity of the PR0213.
- PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide is inhibited.
- either the candidate compound or the PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide is immobilized on a solid support.
- the non-immobilized component carries a detectable label.
- this method comprises the steps of (a) contacting cells and a candidate compound to be screened in the presence of the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide under conditions suitable for the induction of a cellular response normally induced by a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide and (b) determining the induction of said cellular response to determine if the test compound is an effective antagonist.
- the invention provides a method for identifying a compound that inhibits the expression of a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide in cells that express the polypeptide, wherein the method comprises contacting the cells with a candidate compound and determining whether the expression of the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide is inhibited.
- this method comprises the steps of (a) contacting cells and a candidate compound to be screened under conditions suitable for allowing expression of the PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide and (b) determining the inhibition of expression of said polypeptide.
- the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence that encodes a PR0213.
- the isolated nucleic acid molecule comprises a nucleotide sequence having at least about
- sequence identity preferably at least about 81 % sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91 % sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably at least about 99% sequence identity to (a) a DNA molecule encoding a PR0213, PROl 330,
- the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% sequence identity, preferably at least about 81% sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91 % sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably at least about 99% sequence identity
- the invention concerns an isolated nucleic acid molecule comprising a nucleotide sequence having at least about 80% sequence identity, preferably at least about 81 % sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91 % sequence identity, yet more preferably at least about 92% sequence identity vet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably
- soluble extracellular domains of the herein described PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptides are contemplated.
- Another embodiment is directed to fragments of a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474
- polypeptide coding sequence or the complement thereof, that may find use as, for example, hybridization probes, for encoding fragments of a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide that may optionally encode a polypeptide comprising a binding site for an anti-PR0213, anti-PRO 1330, anti-PRO 1449, anti-PR0237, anti-PR0324, anti-PR0351, anti-PR0362, anti-PR0615, anti-PR0531 , anti-PR0538, anti-PR03664, anti-PR0618,
- nucleic acid fragments are usually at least about 20 nucleotides in length, preferably at least about 30 nucleotides in length, more preferably at least about 40 nucleotides in length, yet more preferably at least about 50 nucleotides in length, yet more preferably at least about 60 nucleotides in length, yet more preferably at least about 70 nucleotides in length, yet more preferably at least about 80 nucleotides in length, yet more preferably at least about
- nucleotides in length yet more preferably at least about 100 nucleotides in length, yet more preferably at least about 110 nucleotides in length, yet more preferably at least about 120 nucleotides in length, yet more preferably at least about 130 nucleotides in length, yet more preferably at least about 140 nucleotides in length, yet more preferably at least about 150 nucleotides in length, yet more preferably at least about 160 nucleotides in length, yet more preferably at least about 170 nucleotides in length, yet more preferably at least about 180 nucleotides in length,
- nucleotides in length yet more preferably at least about 190 nucleotides in length, yet more preferably at least about 200 nucleotides in length, yet more preferably at least about 250 nucleotides in length, yet more preferably at least about 300 nucleotides in length, yet more preferably at least about 350 nucleotides in length, yet more preferably at least about 400 nucleotides in length, yet more preferably at least about 450 nucleotides in length, yet more preferably at least about 500 nucleotides in length, yet more preferably at least about 600 nucleotides in length, yet more preferably
- 35 polypeptide-encoding nucleotide sequence may be determined in a routine manner by aligning the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362.
- PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PRO6I 8, PR0772, PRO703, PR0792 or PR0474 polypeptide-encoding nucleotide sequence fragment(s) are novel. All of such PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide-encoding nucleotide sequences are contemplated herein.
- PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide fragments encoded by these nucleotide molecule fragments preferably those PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide fragments that comprise a binding site for an anti-PR0213, anti-PRO 1330, anti- PR01449, anti-PR0237, anti-PR0324, anti-PR0351, anti-PR0362, anti-PR0615, anti-PR0531, anti-PR0538, anti-PR03664, anti-PR0618, anti-PR0772, anti-PRO703, anti-
- the invention provides isolated PR0213, PROl 330, PRO 1449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide encoded by any of the isolated nucleic acid sequences hereinabove identified.
- the invention concerns an isolated PR0213, PROl 330, PRO 1449, PR0237, PR0324,
- PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide comprising an amino acid sequence having at least about 80% sequence identity, preferably at least about 81% sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91 % sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 967c sequence identity, yet
- the invention concerns an isolated PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538.
- PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide comprising an amino acid sequence having at least about 80% sequence identity, preferably at least about 81 % sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 857o sequence identity, yet more preferably at least about 867c sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 887r sequence identity, yet more preferably at least about 897c sequence identity, yet more preferably at least about 907o sequence identity, yet more preferably at least about 91 % sequence identity, yet more preferably at least about 927o sequence identity, yet more preferably at least about 93% sequence identity
- the invention concerns an isolated PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide comprising an amino acid sequence scoring at least about 807c positives, preferably at least about 81 % positives, more preferably at least about 82% positives, yet more preferably at least about 83% positives, yet more preferably at least about 84% positives, yet more preferably at least about 85% positives, yet more preferably at least about 86% positives, yet more preferably at least about 87% positives, yet more preferably at least about 88% positives, yet more preferably at least about 89% positives, yet more preferably at least about 90% positives, yet more preferably at least about 91 % positives, yet more preferably at least about 92% positives, yet more preferably at least about 93% positives, yet more preferably
- the invention provides an isolated PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide without the N-terminal signal sequence and/or the initiating methionine and is encoded by a nucleotide sequence that encodes such an amino acid sequence as hereinbefore described Processes for producing the same are also herein described, wherein those processes comprise cultu ⁇ ng a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of thePR0213, PRO1330 PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide and recovering the PR0213, PROl 330, PRO
- Another aspect of the invention provides an isolated PR021 , PRO 1330, PRO 1449 PR0237, PR0324, PR0 1 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide which is eithei transmembrane domain-deleted or transmembrane domain inactivated Processes foi producing the same are also herein described, wherein those processes comprise cultu ⁇ ng a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PRO ⁇ l 8, PR0772, PRO703, PR0792 or PR0474 polypeptide and recovering the PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351 , PR
- the invention concerns antagonists of a native PR0213, PRO 1330, PRO 1449,
- the antagonist is an ant ⁇ -PR0213, anti-PRO1330, ant ⁇ -PR01449, ant ⁇ -PR0237, ant ⁇ -PR0324, ant ⁇ -PR0351, ant ⁇ -PR0362, ant ⁇ -PR0615, anti- PR0531, ant ⁇ -PR0538, ant ⁇ -PR03664, ant ⁇ -PR0618, ant ⁇ -PR0772, ant ⁇ -PRO703, ant ⁇ -PR0792 or ant ⁇ -PR0474 antibody or a small molecule
- the invention concerns a method of identifying antagonists to a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide which comprise contacting the PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide with a candidate molecule and monitoring a biological activity mediated by said PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide
- the invention concerns a composition of matter comprising a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide, or an antagonist ot a PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide as herein described, or an ant ⁇ -PR0213, ant ⁇ -PRO1330, ant ⁇ -PR01449, anti- PR0237, ant ⁇ -PR0324, ant ⁇ -PR0351 , ant ⁇ -PR0362, ant ⁇ -PR0615, ant ⁇ -PR0531 , ant ⁇ -PR0538.
- the carrier is a pharmaceutically acceptable carrier
- Another embodiment of the present invention is directed to the use ot a PR0213, PROl 330, PROl 449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide, or an antagonist thereof as hereinbefore described, or an ant ⁇ -PR0213, anti- PRO1330, ant ⁇ -PR01449, ant ⁇ -PR0237, ant ⁇ -PR0324, ant ⁇ -PR0351 , ant ⁇ -PR0362, ant ⁇ -PR0615, ant ⁇ -PR0531 , ant ⁇ -PR0538, ant ⁇ -PR03664, ant ⁇ -PR0618, ant ⁇ -PR0772, ant ⁇ -PRO703, ant ⁇ -PR0792 or ant ⁇ -PR0474 antibod ⁇ for the preparation of a medicament useful in the treatment of a condition which is responsive to the PR0213, PRO13
- the invention provides vectors comprising DNA encoding any of the herein described polypeptides
- Host cell comprising any such vector are also provided
- the host cells may be CHO cells, E coli, yeast, or Baculovirus infected insect cells
- a process for producing any of the herein described polypeptides is further provided and comprises cultu ⁇ ng host cells under conditions suitable for expression of the desired polypeptide and recovering the desired polypeptide from the cell culture
- the invention provides chimeric molecules comprising any of the herein described polypeptides fused to a heterologous polypeptide or amino acid sequence
- Example of such chimeric molecules comprise any of the herein described polypeptides fused to an epitope tag sequence or a Fc region of an immunoglobulin
- the invention provides an antibody which specifically binds to any of the above or below described polypeptides
- the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody
- the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences or as antisense probes, wherein those probes may be derived from any of the above or below described nucleotide sequences
- Figure 1 shows the nucleotide sequence (SEQ ID NO 1 ) of a cDNA containing a nucleotide sequence encoding native sequence PR0237, wherein the nucleotide sequence (SEQ ID NO 1 ) is a clone designated herein as DNA34353-1428 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 2 shows the amino acid sequence (SEQ ID NO 2) of a native sequence PR0237 polypeptide as derived from the coding sequence of SEQ ID NO 1
- Figure 3 shows the nucleotide sequence (SEQ ID NO 3) of a cDNA containing a nucleotide sequence encoding native sequence PR0213 wherein the nucleotide sequence (SEQ ID NO 3) is a clone designated herein as DNA30943-1 163 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 4 shows the amino acid sequence (SEQ ID NO 4) of a native sequence PR0213 polypeptide as derived from the coding sequence of SEQ ID NO 3
- Figure 5 shows the nucleotide sequence (SEQ ID NO 5) ot a cDNA containing a nucleotide sequence encoding native sequence PROl 330 wherein the nucleotide sequence (SEQ ID NO 5) is a clone designated herein as DNA64907 1 163 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 6 shows the amino acid sequence (SEQ ID NO 6) of a native sequence PROl 330 polypeptide as derived from the coding sequence ot SEQ ID NO 5
- Figure 7 shows the nucleotide sequence (SEQ ID NO 7) ot a cDNA containing a nucleotide sequence encoding native sequence PRO 1449, wherein the nucleotide sequence (SEQ ID NO 7) is a clone designated herein as DNA64908-1 163 Also presented in bold font and underlined are the positions ot the respective start and stop codons
- Figure 8 shows the amino acid sequence (SEQ ID NO 8) of a native sequence PR01449 polypeptide as derived from the coding sequence of SEQ ID NO 7
- Figure 9 shows the nucleotide sequence (SEQ ID NO 9) of a cDNA containing a nucleotide sequence encoding native sequence PR0324, wherein the nucleotide sequence (SEQ ID NO 9) is a clone designated herein as DNA36343- 1310 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 10 shows the amino acid sequence (SEQ ID NO 10) of a native sequence PR0324 polypeptide as derived from the coding sequence of SEQ ID NO 9
- Figure 1 1 shows the nucleotide sequence (SEQ ID NO 1 1 ) of a cDNA containing a nucleotide sequence encoding native sequence PR0351 , wherein the nucleotide sequence (SEQ ID NO 11 ) is a clone designated herein as DNA40571-1315 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 12 shows the ammo acid sequence (SEQ ID NO 12) of a native sequence PR0351 polypeptide as derived from the coding sequence of SEQ ID NO 1
- Figure 13 shows the nucleotide sequence (SEQ ID NO 13) of a cDNA containing a nucleotide sequence encoding native sequence PR0362, wherein the nucleotide sequence (SEQ ID NO 13) is a clone designated herein as DNA45416 1251 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 14 shows the amino acid sequence (SEQ ID NO 14) of a native sequence PR0362 polypeptide as derived from the coding sequence of SEQ ID NO 13
- Figure 15 shows the nucleotide sequence (SEQ ID NO 15) of a cDNA containing a nucleotide sequence encoding native sequence PR0615, wherein the nucleotide sequence (SEQ ID NO 15) is a clone designated herein as DNA48304-1323 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 16 shows the amino acid sequence (SEQ ID NO 16) of a native sequence PR0615 polypeptide as derived from the coding sequence of SEQ ID NO 15
- Figure 17 shows the nucleotide sequence (SEQ ID NO 17) of a cDNA containing a nucleotide sequence encoding native sequence PR0531 , wherein the nucleotide sequence (SEQ ID NO 17) is a clone designated herein as DNA48 14-1320 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 18 shows the amino acid sequence (SEQ ID NO 18) of a native sequence PR0531 polypeptide as derived from the coding sequence of SEQ ID NO 17
- Figure 19 shows the nucleotide sequence (SEQ ID NO 19) of a cDNA containing a nucleotide sequence encoding native sequence PR0538, wherein the nucleotide sequence (SEQ ID NO 19) is a clone designated herein as DNA48613 1268 Also presented in bold font and underlined are the positions ot the respective stait and stop codons
- Figure 20 shows the amino acid sequence (SEQ ID NO 20) of a native sequence PR0538 polypeptide as derived fiom the coding sequence of SEQ ID NO 19
- Figure 21 shows the nucleotide sequence (SEQ ID NO 21 ) of a cDNA containing a nucleotide sequence encoding native sequence PR03664, wherein the nucleotide sequence (SEQ ID NO 21 ) is a clone designated herein as DNA48614 1268 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 22 shows the amino acid sequence (SEQ ID NO 22) of a native sequence PR03664 polypeptide as derived from the coding sequence of SEQ ID NO 21
- Figure 23 shows the nucleotide sequence (SEQ ID NO 23) of a cDNA containing a nucleotide sequence encoding native sequence PR0618, wherein the nucleotide sequence (SEQ ID NO 23) is a clone designated herein as DNA49152- 1324 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 24 shows the amino acid sequence (SEQ ID NO 24) of a native sequence PR0618 polypeptide as derived from the coding sequence of SEQ ID NO 23
- Figure 25 shows an EST sequence designated herein as DNA35597 (SEQ ID NO 25)
- Figure 26 shows the nucleotide sequence (SEQ ID NO 26) of a cDNA containing a nucleotide sequence encoding native sequence PR0772, wherein the nucleotide sequence (SEQ ID NO 26) is a clone designated herein as DNA49645 1347 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 27 shows the amino acid sequence (SEQ ID NO 27) of a native sequence PR0772 polypeptide as derived from the coding sequence of SEQ ID NO 26
- Figure 28 shows the nucleotide sequence (SEQ ID NO 28) of a cDNA containing a nucleotide sequence encoding native sequence PRO703, wherein the nucleotide sequence (SEQ ID NO 28) is a clone designated herein as DNA50913-1287 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 29 shows the amino acid sequence (SEQ ID NO 29) of a native sequence PRO703 polypeptide as derived from the coding sequence of SEQ ID NO 28
- Figure 30 shows the nucleotide sequence (SEQ ID NO 30) of a cDNA containing a nucleotide sequence encoding native sequence PR0792, wherein the nucleotide sequence (SEQ ID NO 30) is a clone designated herein as DNA56352-1358 Also presented in bold font and underlined are the positions of the respective start and stop codons
- Figure 31 shows the amino acid sequence (SEQ ID NO 31 ) of a native sequence PR0792 polypeptide as derived from the coding sequence of SEQ ID NO 30
- Figure 32 shows the nucleotide sequence (SEQ ID NO 32) of a cDNA containing a nucleotide sequence encoding native sequence PR0474, wherein the nucleotide sequence (SEQ ID NO 32) is a clone designated herein as DNA56045-1380 Also presented in bold font and underlined are the positions ot the respective start and stop codons
- Figure 33 shows the amino acid sequence (SEQ ID NO 33) of a native sequence PR0474 polypeptide as derived from the coding sequence of SEQ ID NO 32 Detailed Description of the Invention I Definitions
- gene amplification and “gene duplication” are used interchangeably and refer to a process by which multiple copies of a gene or gene fragment are formed in a particular cell or cell line
- the duplicated region (a stretch of amplified DNA) is often referred to as "amphcon " Usually, the amount of the messenger RNA
- Tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues
- cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth
- cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia More particular examples of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, ghoblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colorectal cancer, endometnal carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer
- Treatment is an intervention performed with the intention of preventing the development or altering the pathology of a disorder
- treatment refers to both therapeutic treatment and prophylactic or preventati ve measures
- Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented
- a therapeutic agent may directly decrease the pathology of tumor cells, or render the tumor cells more susceptible to treatment by other therapeutic agents, e g , radiation and/or chemotherapy
- the "pathology" of cancer includes all phenomena that compromise the well-being of the patient This includes, without limitation, abnormal or uncontrollable cell growth, metastasis, interference with the normal functioning of neighboring cells, release of cytokines or other secretory products at abnormal levels, suppression or aggravation of inflammatory or immunological response, etc
- “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cattle, pigs, sheep, etc
- the mammal is human
- Carriers as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed
- the physiologically acceptable carrier is an aqueous pH buffered solution
- physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids, antioxidants including ascorbic acid low molecular weight (less than about 10 residues) polypeptides, proteins, such as serum albumin, gelatin, oi immunoglobulins, hydrophilic polymeis such as polyvinylpyrrohdone, amino acids such as glycine, glutamine, asparagine, argimne oi lysine monosacc
- cytotoxic agent refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells
- the term is intended to include radioactive isotopes (e g., I 131 , I l2 ⁇ Y 9 " and Re 186 ), chemotherapeutic agents, and toxins such as enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof
- chemotherapeutic agent is a chemical compound useful in the treatment of cancer
- chemotherapeutic agents include ad ⁇ amycin, doxorubicin, epirubicin, 5-fluorourac ⁇ l, cytosine arabinoside ("Ara- C"), cyclophosphamide, thiotepa, busulfan, cytoxin, taxoids, e g , paclitaxel (Taxol, B ⁇ stol-Myers Squibb Oncology, Princeton, NJ), and doxetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, Rnace), toxotere, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, lfosfamide, mitomycin C, mitoxantrone, vinc ⁇ stine, vinorelbine, carboplatin, teniposide, daunomy
- a “growth inhibitory agent” when used herein refers to a compound or composition which inhibits growth of a cell, especially cancer cell overexpressing any of the genes identified herein, either in vttio or in vivo
- the growth inhibitory agent is one which significantly reduces the percentage of cells overexpressing such genes in S phase
- growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce Gl arrest and M-phase arrest
- Classical M-phase blockers include the vincas (vinc ⁇ stine and vinblastine), taxol, and topo II inhibitors such as doxorubicin, epirubicin, daunorubicm, etoposide, and bleomycin
- Those agents that arrest Gl also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5- fluorouracil
- Doxorubicin is an anthracychne antibiotic
- the full chemical name of doxorubicin is (8S-c ⁇ s)-10-[(3- am ⁇ no-2,3,6-t ⁇ deoxy- ⁇ -L-lyxo-hexapyranosyl)oxy]-7,8,9,10-tetrahyd ⁇ o-6,8,l l -t ⁇ hydroxy-8-(hydroxyacetyl)-l - methoxy-5 , 12-naphthacened ⁇ one
- cytokine is a generic term for proteins released by one cell population which act on anothei cell as intercellular mediators Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones Included among the cytokines are growth hormone such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsuhn, relaxin, prorelaxin, glycoprotein hormones such as
- nerve growth factors such as NGF- ⁇ , platelet- growth factor, transforming growth tactois (TGFs) such as TGF- ⁇ and TGF- ⁇ , insulin-like growth factor-I and -II, erythropoietin (EPO), osteoinductive factors, interferons such as interferon -a, - ⁇ , and - ⁇ , colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF), granulocyte-macrophage-CSF (GM-CSF), and granulocyte-CSF (G- CSF), interleukins (ILs) such as IL-1 , IL- 1 a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11 , IL-12, a tumor necrosis factor such as TNF- ⁇ or TNF- ⁇ , and other polypeptide factors including LIF and kit ligand (KL) As used heiein
- prodrug refers to a precursor or derivative form of a pharmaceutically active substance that is less cytotoxic to tumor cells compared to the parent drug and is capable of being enzymatically activated or converted into the more active parent form See, e g , Wil an, "Prodrugs in Cancer Chemotherapy", Biochemical Society Transactions.
- the prodrugs of this invention include, but are not limited to, phosphate- containing prodrugs, thiophosphate-contaimng prodrugs, sulfate-containing prodrugs, peptide-contaimng prodrugs, D-amino acid-modified prodrugs, glysocylated prodrugs, ⁇ -lactam-contaimng prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 5- fluorocytosine and other 5-fluorou ⁇ d ⁇ ne prodrugs which can be converted into the more active cytotoxic free drug Examples of cytotoxic drugs that can be
- an “effective amount” of a polypeptide disclosed herein or an antagonist thereof, in reference to inhibition of neoplastic cell growth, tumor growth or cancer cell growth is an amount capable of inhibiting, to some extent, the growth of target cells
- the term includes an amount capable of invoking a growth inhibitory, cytostatic and/or cytotoxic effect and/or apoptosis of the target cells
- An “effective amount” of a PRO polypeptide antagonist for purposes of inhibiting neoplastic cell growth, tumor growth or cancer cell growth may be determined empirically and in a routine manner
- a “therapeutically effective amount”, in reference to the treatment ot tumor, refers to an amount capable of invoking one or more of the following effects ( 1 ) inhibition, to some extent, of tumor growth, including, slowing down and complete growth arrest, (2) reduction in the number of tumor cells, (3) reduction in tumor size, (4) inhibition (( e , reduction, slowing down or complete stopping) of tumor cell infiltration into peripheral organs, (5) inhibition (( e , reduction, slowing down or complete stopping) ot metastasis, (6) enhancement of anti-tumor immune response, which may, but does not have to, result in the regression or rejection of the tumor, and/or (7) relief, to some extent, of one or more symptoms associated w ith the disorder
- a "therapeutically effective amount" of a PRO polypeptide antagonist for purposes of treatment of tumor may be determined empirically and in a routine mannei
- a “growth inhibitory amount” of a PRO antagonist is an amount capable of inhibiting the growth of a cell, especially tumor, e g , cancer cell, either in vitro or in vivo
- a “growth inhibitory amount” of a PRO antagonist foi purposes of inhibiting neoplastic cell growth may be determined empirically and in a routine mannei
- a "cytotoxic amount” of a PRO antagonist is an amount capable of causing the destruction ot a cell, especially tumor, e g , cancer cell, either in vitw o ⁇ in vivo
- a "cytotoxic amount" of a PRO antagonist for strig poses of inhibiting neoplastic cell growth may be determined empi ⁇ callv and in a routine manner
- PRO polypeptide and "PRO” as used herein and when immediately followed by a numerical designation refer to various polypeptides, wherein the complete designation (i e , PRO/number) refers to specific polypeptide sequences as described herein
- PRO/number polypeptide and “PRO/number” wherein the term “number” is provided as an actual numerical designation as used herein encompass native sequence polypeptides and polypeptide variants (which are further defined herein)
- the PRO polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods
- a “native sequence PRO polypeptide” comprises a polypeptide having the same ammo acid sequence as the corresponding PRO polypeptide derived from nature Such native sequence PRO polypeptides can be isolated from nature or can be produced by recombinant or synthetic means
- the term "native sequence PRO polypeptide” specifically encompasses naturally-occurring truncated or secreted forms of the specific PRO polypeptide (e g , an extracellular domain sequence), naturally-occurring variant forms (e g , alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide
- the native sequence PRO polypeptides disclosed herein are mature or full-length native sequence polypeptides comprising the full-length amino acids sequences shown in the accompanying figures Start and stop codons are shown in bold font and underlined in the figures However, while the PRO polypeptide disclosed in the accompanying figures are shown to begin with methionine residues designated herein as amino acid position 1 in the figures, it is conceivable
- the PRO polypeptide "extracellular domain” or “ECD” refers to a form of the PRO polypeptide which is essentially free of the transmembrane and cytoplasmic domains Ordinarily, a PRO polypeptide ECD will have less than 1 c of such transmembrane and/or cytoplasmic domains and preferably, will have less than 0 57c of such domains It will be understood that any transmembrane domains identified for the PRO polypeptides of the present invention are identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic domain The exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified herein Optionally, therefore, an extracellular domain of a transmembrane domain of a
- PRO polypeptide may contain from about 5 or fewer amino acids on either side of the transmembrane domain/extracellular domain boundary as identified in the Examples or specification and such polypeptides, with or without the associated signal peptide, and nucleic acid encoding them, are comtemplated by the present invention
- PRO variant polypeptides are at least about 10 amino acids in length, often at least about 20 amino acids in length, more often at least about 30 amino acids in length, more often at least about 40 amino acids in length, more often at least about 50 amino acids in length, more often at least about 60 amino acids
- amino acids in length more often at least about 70 amino acids in length more often at least about 80 amino acids in length more often at least about 90 amino acids in length, more often at least about 100 amino acids in length more often at least about 150 amino acids in length, more often at least about 200 amino acids in length, more often at least about 300 amino acids in length, or more
- Table 1 provides the complete source code for the ALIGN-2 sequence comparison
- This source code may be routinely compiled tor use on a UNIX operating system to provide the ALIGN-2 sequence comparison computer program
- Tables 2A 2D show hypothetical exemplifications for using the below described method to determine % amino acid sequence identity (Tables 2A-2B) and % nucleic acid sequence ⁇ dent ⁇ t ⁇ (Tables 2C 2D) using the ALIGN-2 sequence comparison computer program, wherein "PRO represents the amino acid sequence
- Comparison Protein represents the amino acid sequence of a polypeptide against which the "PRO polypeptide of interest is being compared
- PRO-DNA represents a hypothetical PRO-encoding nucleic acid sequence of interest
- Comparison DNA represents the nucleotide sequence of a nucleic acid molecule against which the "PRO DNA” nucleic acid molecule of interest is being compared
- "X", "Y ' and “Z ' each repiesent different hypothetical amino acid residues and "N", L and ' V each represent different hypothetical nucleotides.
- Max file length is 65535 (limited by unsigned short x in the jmp struct)
- a sequence with 1/3 or more of its elements ACGTU is assumed to be DNA
- the program may create a tmp file in /tmp to hold info about traceback
- static nm, /* matches in core - for checking */ static lmax, /* lengths of stripped file names */ static ⁇ j[2], /* jmp index for a path */ static nc[2] , /* number at start of current line */ static m[2] , /* current elem number — for gapping */ static s ⁇ z[2], static char *ps[2], /* ptr to current element */ static char *po[2], /* ptr to next output char slot */ static char out[2][P LINE] /* output line */ static char star[P LINE], /* set by starsQ */
- *ps[ ⁇ ] toupper(*ps[ ⁇ ]), po[ ⁇ ] + + , ps[ ⁇ ] + + ,
- *py+ + *px; else if ( ⁇ slower(*px))
- *py+ + toupper(*px); if ( ⁇ ndex("ATGCU",*(py-l))) natgc+ + ; ⁇ ⁇
- Page 2 ofnwsubr.c ...readjmps if 0 ⁇ 0 && dx[dmax]. offset && fj) ⁇
- Percent (%) amino acid sequence identity' with respect to the PRO polypeptide sequences identified herein is defined as the percentage of ammo acid residues in a candidate sequence that are identical with the amino acid residues in a PRO sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Mega gn (DNASTAR) software Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared For purposes herein, however, % amino acid sequence identity values are obtained as described below by using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 The ALIGN-2 sequence comparison computer program was authored by Genentech
- % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows
- % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows
- a % amino acid sequence identity value is determined by dividing (a) the number of matching identical amino acids residues between the amino acid sequence of the PRO polypeptide of interest having a sequence derived from the native PRO polypeptide and the comparison amino acid sequence of interest (J e , the sequence against which the PRO polypeptide of interest is being compared which may be a PRO variant polypeptide) as determined by WU-BLAST-2 by (b) the total number of amino acid residues of the PRO polypeptide of interest
- J e the sequence against which the PRO poly
- PRO variant polynucleotides are at least about 30 nucleotides in length, often at least about 60 nucleotides in length, more often at least about 90 nucleotides in length, more often at least about 120 nucleotides in length, more often at least about 150 nucleotides in length, more often at least about 180 nucleotides in length, more often at least about 210 nucleotides in length, more often at least about 240 nucleotides in length, more often at least about 270 nucleotides in length, more often at least about 300 nucleotides in length, more often at least about 450 nucleotides in length, more often at least about 600 nucleotides in length, more often at least about 900 nucleotides in length, or more
- Percent (%) nucleic acid sequence identity with respect to the PRO polypeptide-encoding nucleic acid sequences identified herein is defined as the percentage of nucleotides in a candidate sequence that are identical with the nucleotides in a PRO polypeptide-encoding nucleic acid sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity Alignment for purposes ot determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megahgn (DNASTAR) software Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared For purposes herein, however, % nucleic acid sequence identity values are obtained as described below by using the sequence comparison computer program ALIGN-2, wherein the complete source code tor the ALIGN-2 program is provided in Table 1 The ALIGN
- the % nucleic acid sequence ⁇ dent ⁇ t ⁇ ot a given nucleic acid sequence C to, with, oi against a given nucleic acid sequence D (which can alternativeh be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid sequence identity to v. ith or against a given nucleic acid sequence D) is calculated as follows
- % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D is calculated as follows
- a % nucleic acid sequence identity value is determined by dividing (a) the numbei ot matching identical nucleotides between the nucleic acid sequence of the PRO polypeptide encoding nucleic acid molecule ot interest having a sequence derived from the native sequence PRO polypeptide-encoding nucleic acid and the comparison nucleic acid molecule of interest (i e , the sequence against which the PRO polypeptide-encoding nucleic acid molecule of interest is being compared which may be a variant PRO polynucleotide) as determined by WU-BLAST-2 by (b) the total number of nucleotides of the PRO polypeptide- encoding nucleic acid molecule of interest
- the nucleic acid sequence A is the comparison nucleic acid molecule of interest
- isolated when used to describe the various polypeptides disclosed herein, means polypeptide that has been identified and separated and/or recovered from a component of its natural environment Preferably, the isolated polypeptide is free of association with all components with which it is naturally associated Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes
- the polypeptide will be purified ( 1 ) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducmg oi reducing conditions using Coomassie blue oi, preferably, silver stain Isolated polypeptide includes polypeptide in situ within recombinant eel Is, since at least one component ot the PRO natural environment will not be present Ordinarily, however, isolated polypeptide
- an "isolated" nucleic acid molecule encoding a PRO polypeptide or an 'isolated” nucleic acid encoding an anti-PRO antibody is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the PRO-encoding nucleic acid or the anti-PRO-encoding nucleic acid Preferably, the isolated nucleic acid is free of association with all components with which it is naturally associated
- An isolated PRO-encoding nucleic acid molecule or an anti- PRO-encoding nucleic acid molecule is other than in the form or setting in which it is found in nature Isolated nucleic acid molecules therefore are distinguished from the PRO-encoding nucleic acid molecule or the anti-PRO- encoding nucleic acid molecule as it exists in natural cells
- an isolated nucleic acid molecule encoding a PRO polypeptide or an anti-PRO antibody includes PRO-encoding nucleic acid molecules and anti-PRO-encoding
- control sequences refers to DNA sequences necessary for the expression of an operably linked coding sequence in a pai ticular host organism
- the control sequences that are suitable for prokaryotes include a promoter, optionally an operator sequence, and a ⁇ bosome binding site
- Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers
- Nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence
- DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide
- a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence
- a ⁇ bosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation
- "operably linked' means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase
- enhancers do not have to be contiguous Linking is accomplished by ligation at convenient restriction sites If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice
- antibody is used in the broadest sense and specifically covers, for example, single anti- PR0213, anti-PRO 1330, anti-PRO 1449, ant ⁇ -PR0237, anti PR0324, ant ⁇ -PR0351 ant ⁇ -PR0362, ant ⁇ -PR0615, ant ⁇ -PR0531, ant ⁇ -PR0538, ant ⁇ -PR03664, ant ⁇ -PR0618, ant ⁇ -PR0772 ant ⁇ -PRO703, ant ⁇ -PR0792 or anti- PR0474 monoclonal antibodies (including antagonist and neutralizing ant ⁇ bod ⁇ es),ant ⁇ -PR0213, anti PRO1330, anti-PRO 1449, ant ⁇ -PR0237, ant ⁇ -PR0324, ant ⁇ -PR0351 , ant ⁇ -PR0362, anti PR0615, ant ⁇ -PR0531 , ant ⁇ -PR0538, ant ⁇ -PR03664, ant ⁇ -PR0618, anti PR0772, ant ⁇ -PRO703, anti
- “Stringency” of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures Hybridization generally depends on the ability of denatured DNA to reanneal when complementar) strands are present in an environment below their melting temperature The higher the degree of desired homology between the probe and hyb ⁇ dizable sequence, the higher the relative temperatuie which can be used As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so For additional details and explanation of stringency of hybridization reactions, see Ausubel et al , Current Protocols in Molecular Biology, Wiley Interscience Publishers, (1995)
- “Stringent conditions” or “high stringency conditions”, as defined herein, may be identified by those that ( 1 ) employ low ionic strength and high temperature for washing, for example 0 015 M sodium chlo ⁇ de/0 0015 M sodium c ⁇ trate/0 1 % sodium dodecyl sulfate at 50°C, (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0 1 % bovine serum albumin/0 1 % F ⁇ coll/0 1 % polyv ⁇ nylpyrrol ⁇ done/50mM sodium phosphate buffer at pH 6 5 with 750 M sodium chloride, 75 mM sodium citrate at 42°C, or (3) employ 50% formamide, 5 x SSC (0 75 M NaCI, 0 075 M sodium citrate), 50 mM sodium phosphate (pH 6 8), 0 1% sodium pyrophosphate, 5 x Denhardt's solution, sonicated salmon sperm
- Modely stringent conditions may be identified as described by Sambrook et al , Molecular Cloning A Laboratory Manual. New York Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e g , temperature, ionic strength and % SDS) less stringent than those described above
- An example of moderately stringent conditions is overnight incubation at 37°C in a solution comprising 20% formamide, 5 x SSC (150 mM NaCl, 15 mM t ⁇ sodium citrate), 50 mM sodium phosphate (pH 7 6), 5 x Denhardt s solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed by washing the filters in 1 x SSC at about 35°C-50°C
- the skilled artisan will recognize how to adjust the temperature, ionic strength etc as necessary to accommodate factors such as probe length and the like
- the term ' epitope tagged when used herein refers to a chimeric
- tag polypeptide has enough residues to provide an epitope against which an antibody can be made, yet is short enough such that it does not interfere with activity of the polypeptide to which it is fused
- the tag polypeptide preferably also is fairly unique so that the antibody does not substantially cross-react with other epitopes
- Suitable tag polypeptides generally have at least six amino acid residues and usually between about 8 and 50 ammo acid residues (preferably, between about 10 and 20 ammo acid residues)
- Active refers to form(s) ot PR0213, PRO 1330, PRO 1449, PR0237 PR0324, PR0351 , PRO-362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptides which retain a biological and/or an immunological activity/property of a native or naturally- occurring PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide, wherein "biological” activity refers to a function (either inhibitory or stimulatory) caused by a native or naturally-occurring PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 .
- Bio activity in the context of an antibody or another antagonist molecule that can be identified by the screening assays disclosed herein (e g , an organic or inorganic small molecule, peptide, etc ) is used to refer to the ability of such molecules to bind or complex with the polypeptides encoded by the amplified genes identified herein, or otherwise interfere with the interaction of the encoded polypeptides with other cellular proteins oi otherwise interfere with the transcription or translation of a PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide
- a preferred biological activity is growth inhibition of a target tumor cell
- Another preferred biological activity is cytotoxic activity resulting in the death of the target tumor cell
- biological activity in the context of a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide means the ability of aPRO213, PRO1330, PRO1449 PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide to induce neoplastic cell growth or uncontrolled cell growth
- immunological cross-reactivity means immunological cross-reactivity with at least one epitope of a PR0213, PROl 330, PR01449, PR0237. PR0324, PR0351. PR0362, PR0615, PR0531 , PR0538, PR03664.
- PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide "Immunological cross-reactivity" as used herein means that the candidate polypeptide is capable of competitively inhibiting the qualitative biological act ⁇ v ⁇ t> ot a PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide having this activity with polyclonal antisera raised against the known active PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772.
- PRO703, PR0792 or PR0474 polypeptide Such antisera are piepared in conventional fashion by meeting goats or rabbits, for example, subcutaneously with the known active analogue in complete Freund's ad)uvant, followed by booster lntrape ⁇ toneal or subcutaneous injection in incomplete Freunds
- the immunological cross-reactivity preferably is ' specific", which means that the binding affinity of the immunologically cross-reactive molecule (e g , antibody) identified, to the corresponding PR0213, PROl 330, PRO 1449, PR0237, PR0324, PR0351.
- PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide is significantly higher (preferably at least about 2-t ⁇ mes, more preferably at least about 4-t ⁇ mes, even more preferably at least about 8-t ⁇ mes, most preferably at least about 10-t ⁇ mes higher) than the binding affinity of that molecule to any other known native polypeptide
- antagonist is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native PR0213 , PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide disclosed herein or the transcription or translation thereof
- Suitable antagonist molecules specifically include antagonist antibodies or antibody fragments, fragments, peptides, small organic molecules, anti-sense nucleic acids, etc Included are methods for identifying antagonists of a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the
- “Native antibodies” and “native immunoglobulins” are usually heterotetrame ⁇ c glycoproteins of about 150,000 daltons. composed of two identical light (L) chains and two identical heavy (H) chains Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes Each heavy and light chain also has regularly spaced intrachain disulfide bridges Each heavy chain has at one end a variable domain (V H ) followed by a number of constant domains Each light chain has a variable domain at one end (V L ) and a constant domain at its other end, the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light-chain variable domain is aligned with the variable domain of the heavy chain Particular amino acid residues are believed to form an interface between the light- and heavy-chain variable domains
- variable refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody tor its particular antigen
- CDRs complementarity-determining regions
- hyperva ⁇ able regions both in the light-chain and the heavy-chain variable domains
- the more highly conserved portions ot variable domains are called the framework (FR) regions
- the variable domains of native heavy and light chains each comprise four FR regions, largely adopting a ⁇ -sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the ⁇ -sheet structure
- the CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al , NIH Publ No 91-3242, Vol I, pages 647-669 (1991 ))
- the constant domains see Kabat et al , NIH Publ No 91-3
- hyperva ⁇ able region when used herein refers to the amino acid residues of an antibody which are responsible for antigen-binding
- the hyperva ⁇ able region comprises amino acid residues from a "complementarity determining region" or "CDR" (; e , residues 24-34 (Ll ), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and 31-35 (HI), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain, Kabat et al , Sequences of Proteins of Immunological Interest, 5th Ed Public Health Service, National Institute of Health, Bethesda, MD [ 1991 ]) and/or those residues from a "hyperva ⁇ able loop" (t e , residues 26-32 (Ll ), 50-52 (L2) and 91-96 (L3) in the light chain variable domain and 26 32 (HI ), 53-55 (H2) and 96-101 (H3) in the heavy chain variable domain , Clothia and Lesk
- Antibody fragments comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody
- antibody fragments include Fab, Fab', F(ab') 2 , and Fv fragments, diabodies , linear antibodies (Zapata et al , Protein Eng .8(10) 1057- 1062 [ 1995]) , single-chain antibody molecules, and multispecific antibodies formed from antibody fragments
- Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual "Fc” fragment, whose name reflects its ability to crystallize readily Pepsin treatment yields an F(ab') 2 fragment that has two antigen-combining sites and is still capable of cross-linking antigen
- Fv is the minimum antibody fragment which contains a complete antigen-recognition and -binding site This region consists of a dimer of one heavy- and one light chain variable domain in tight, non covalent association It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V H -V L dimer Collectively, the six CDRs confer antigen binding specificity to the antibody However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site
- the Fab fragment also contains the constant domain of the light chain and the first constant domain (CH 1 ) of the heavy chain Fab fragments differ from Fab' fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH 1 domain including one or more cysteines from the antibody hinge region Fab'-SH is the designation herein for Fab in which the cysteine res ⁇ du
- immunoglobulins can be assigned to one of two clearly distinct types, called kappa (K) and lambda ( ⁇ ) based on the amino acid sequences of their constant domains Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes There are five major classes of immunoglobulins IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e g , IgG 1 , IgG2, IgG3, IgG4, IgA, and IgA2
- the heavy-chain constant domains that correspond to the different classes of immunoglobulins are called ⁇ , ⁇ , e, ⁇ , and ⁇ , respectively
- the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known
- the term "monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, t e , the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts Monoclonal antibodies are highly specific, being directed against a single antigenic site Furthermore, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen In addition to their specificity, the monoclonal antibodies are advantageous in that they are synthesized by the hyb ⁇ doma culture, uncontaminated by other immunoglobulins The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hyb ⁇ dom
- the monoclonal antibodies herein specifically include ' chimeric antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the cha ⁇ n(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments ot such antibodies, so long as they exhibit the desired biological activity (U S Patent No 4,816,567, Morrison et al , Proc Natl Acad Sci USA, 8i 6851 -6855 [1984])
- Humanized forms of non-human (e g , murine) antibodies are chimeric immunoglobulins, lmmunoglobulm chains or fragments thereof (such as Fv, Fab, Fab F(ab )., or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin
- humanized antibodies are human immunoglobulins (recipient antibod ⁇ ) in which residues from a CDR ot the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity
- donor antibody such as mouse, rat or rabbit having the desired specificity, affinity, and capacity
- Fv FR residues ot the human immunoglobulin are replaced by corresponding non human residues
- humanized antibodies ma comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences
- Single-chain Fv or “sFv” antibody fragments comprise the V H and V L domains of antibody, wherein these domains are present in a single polypeptide chain
- the Fv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the sFv to form the desired structure for antigen binding
- diabodies refers to small antibody fragments with two antigen-binding sites, which fragments compiise a heavy-chain variable domain (V H ) connected to a light-chain variable domain (V L ) in the same polypeptide chain (V H - V L )
- V H heavy-chain variable domain
- V L light-chain variable domain
- an “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes
- the antibody will be purified (1 ) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use ot a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present Ordinarily, howe ⁇ e ⁇ , isolated antibody will be prepared by at least one purification step
- label when used herein refers to a detectable compound oi composition which is conjugated directly or indirectly to the antibody so as to generate a "labeled antibody
- the label may be detectable by itself (e g . radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable Radionuchdes that can serve as detectable labels include, for example, 1-131 , 1-123, 1-125, Y-90, Re- 188, Re- 186, At-21 1 , Cu-67, B ⁇ -212, and Pd- 109
- the label may also be a non-detectable entity such as a toxin
- solid phase is meant a non-aqueous matrix to which the antibody of the present invention can adhei e
- solid phases encompassed herein include those formed partially or entirely of glass (e ? controlled pore glass), polysaccha ⁇ des (e g , agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones
- the solid phase can comprise the well of an assay plate, in otheis it is a purification column (e g , an affinity chromatographv column) This term also includes a discontinuous solid phase of discrete particles, such as those described in U S Patent No 4,275,149
- a "hposome” is a small vesicle composed of various types of hpids, phosphohpids and/or surfactant which is useful for delivery of a drug (such as a PR0213, PROl 330, PRO 1449, PR0237, PR0324, PR0351 , PR0362,
- the components of the hposome are commonly arranged in a bilayer formation, similar to the hpid arrangement of biological membranes
- immunoadhesin designates antibody-like molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains Structurally, the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (t e , is “heterologous"), and an immunoglobulin constant domain sequence
- the adhesin part of an immunoadhesin molecule typically is a contiguous am o acid sequence comprising at least the binding site of a receptor or a ligand
- the immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG- 1 , IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM
- PRQ213. PRO 1330. PRO 1449. PRQ237. PRQ324. PRQ351. PRQ362. PRQ615. PRQ531. PRQ538. PRQ3664. PRQ618. PRQ772. PRO703. PRQ792 and PRQ474 polypeptides
- the present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PRO ⁇ l 5, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 and PR0474
- cDNA encoding PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 and PR0474 polypeptides has been identified and isolated, as disclosed in further detail in the Examples below It is noted that proteins produced in separate expression rounds may be given different PRO numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed However, for sake of simplicity, in the present specification the proteins encoded by the herein disclosed nucleic acid sequences as well as all
- cDNA clones have been deposited with the ATCC
- the actual nucleotide sequence of the clones can readily be determined by the skilled artisan by sequencing of the deposited clone using routine methods in the art
- the predicted amino acid sequences can be determined from the nucleotide sequences using routine skill For the PR0213. PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531.
- PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptides and encoding nucleic acid described herein Applicants have identified what are believed to be the reading frames best identifiable with the sequence information available at the time B PRQ213, PRO 1330, PRO 1449. PRQ237. PRQ324. PRQ351. PRQ362, PRQ615. PRQ531. PRQ538. PRQ3664. PRQ618. PRQ772. PRO703. PRQ792 and PRQ474 Variants
- PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 and PR0474 polypeptides described herein it is contemplated that PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PRO ⁇ l 8, PR0772, PRO703, PR0792 andPR0474 variants can be prepared PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PRO ⁇ l 8, PR0772, PRO703, PR0792 and PR0474 variants can be prepared by introducing appropriate nucleotide changes into the PR0213, PRO1330, PR01449, PR0237
- the variation is by substitution ot at least one am o acid with any other amino acid in one or more of the domains of the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474
- the variation is by substitution ot at least one am o acid with any other amino acid in one or more of the domains of the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474
- Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the PR
- PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 and PR0474 polypeptide fragments are provided herein Such fragments may be truncated at the N-terminus or C-terminus, or may lack internal residues, for example, when compared with a full-length native protein Certain fragments lack ammo acid residues that are not essential for adesired biological activity of the PR0213, PROl 330, PRO1449, PR0237, PR0324, PR0351 , PRO362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide
- PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 fragments may be prepared by any of a number of conventional techniques Desired peptide fragments may be chemically synthesized
- An alternative approach involves generating PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 fragments by enzymatic digestion, e g , by treating the protein with an enzyme known to cleave proteins at sites defined by particular amino acid residues, or by digesting the DNA with suitable restriction enzymes and isolating the desired fragment
- Yet another suitable technique involves isolating and amplifying a DNA fragment encoding a desired polypeptide fragment,
- PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide fragments share at least one biological and/or immunological activity with the native PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide
- conservative substitutions of interest are shown in Table 3 under the heading of preferred substitutions If such substitutions result in a change in biological activity, then more substantial changes, denominated exemplary substitutions in Table 3, or as f ui ther described below in reference to amino acid classes, are introduced and the products screened
- Substantial modifications in function or immunological identity of the polypeptide are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area ot the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain Naturally occurring residues are divided into groups based on common side-chain properties
- Non conservative substitutions will entail exchanging a member ot one ot these classes for another class
- Such substituted residues also may be introduced into the conservative substitution sites or, more preferably, into the remaining (non conserved) sites
- Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence
- preferred scanning amino acids are relatively small, neutral ammo acids
- amino acids include alanine, glycine, serine, and cysteine
- Alanine is typically a preferred scanning amino acid among this group because it eliminates the side-chain beyond the beta-carbon and is less likely to alter the main-chain conformation of the variant [Cunningham and Wells, Science, 244 1081-1085 (1989)]
- Alanine is also typically preferred because it is the most common amino acid Further, it is frequently found in both buried and exposed positions [Creighton, The Proteins, (W H Freeman & Co , N Y ), Chothia, J Moi Biol , 150 1 (1976)] If alanine substitution does not yield adequate amounts of variant, an lsote ⁇ c amino acid can be used
- PRQ213. PRO1330. PRQ1449. PRQ237. PRQ324. PRQ351. PRQ362. PRQ615. PRQ531. PRQ538. PRQ3664. PRQ618. PRQ772. PRO703. PRQ792 and PRQ474
- Covalent modifications of PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 and PR0474 are included within the scope of this invention
- One type of covalent modification includes reacting targeted amino acid residues of aPR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide with an organic de ⁇ vatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or
- Another type of covalent modification of the PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 orPR0474 polypeptide included within the scope of this invention comprises altering the native glycosylation pattern of the polypeptide "Altering the native glycosylation pattern' is intended for purposes herein to mean deleting one or more carbohydrate moieties found in native sequence PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 (either by removing the underlying glycosylation site or by deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that are not present in the native sequence PR02
- PR0362, PR0615, PR0531, PR0538, PR03664, PRO ⁇ l 8, PR0772, PRO703, PR0792 or PR0474 polypeptide may be accomplished by alte ⁇ ng the amino acid sequence
- the alteration may be made, for example, by the addition of, or substitution by, one or more serine or threonine residues to the native sequence PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 (for O linked glycosylation sites)
- the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 amino acid sequence may optionally be altered through changes at the DNA level, particularly by mutating the
- Another means of increasing the number of carbohydrate moieties on the PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703 PR0792 or PR0474 polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide Such methods are described in the art, e g , in WO 87/05330 published 1 1 September 1987, and in Aphn and W ⁇ ston CRC C ⁇ t Rev Biochem . pp 259 306 (1981 )
- Removal of carbohydrate moieties present on the PR0213, PRO 1330, PR01449, PR0237 PR0324 PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide may be accomplished chemically or enzymatically or by mutational substitution ot codons encoding for amino acid residues that serve as targets for glycosylation
- Chemical deglycosylation techniques are known in the art and described, for instance, by Hakimuddm, et al , Arch Biochem Biophys , 259 52 (1987) and by Edge et al , Anal Biochem .
- Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo and exo-glycosidases as described by Thotakura et al , Meth Enzymol 138 350 (1987)
- PR0213, PRO 1330, PR01449, PR0237 PR0324, PR0351 PR0362, PR0615, PR0531 , PR0538 PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 comprises linking the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide to one ot a variety of nonproteinaceous polymers, e g , polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U S Patent Nos 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791 ,192 or 4,179,337
- PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 of the present invention may also be modified in a way to form a chimeric molecule comprising PR0213, PROl 330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 fused to another, heterologous polypeptide or ammo acid sequence
- such a chimeric molecule comprises a fusion of the PR0213, PROl 330, PROl 449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 with a tag polypeptide which provides an epitope to which an anti-tag antibody can selectively bind
- the epitope tag is generally placed at the amino- or carboxyl-terminus of the PR0213, PROl 330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474
- the presence of such epitope-tagged forms ot the PR0213, PROl 330, PROl 449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531, PR0538, PR03
- Tag polypeptides include the Flag- peptide [Hopp et al , BioTechnology, 6 1204-1210 (1988)].
- the chimeric molecule mav comprise a fusion of the PR0213, PROl 330
- the immunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge, CHI , CH2 and CH3 regions ot an IgG l molecule For the production ot immunoglobulin
- PRO1330 PR01449. PRQ237. PRQ324. PRQ351. PR0362. PR Q 615, PRQ531. PRQ538. PRQ3664. PRQ618. PRQ772. PRO703. PRQ792 and PRQ474 Polypeptides
- PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 by cultu ⁇ ng cells transformed or transfected with a vector containing PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 nucleic acid
- alternative methods which are well known in the art, may be employed to prepare PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474
- alternative methods which are well known in the art, may be employed to prepare PR0213
- In vitro protein synthesis may be performed using manual techniques or by automation Automated synthesis may be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster City, CA) using manufacturer's instructions
- Various portions of thePRO213,PRO1330, PRO1449,PRO237, PRO324, PRO351, PRO362, PRO615, PRO531 , PRO538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the full-length PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474
- PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 may be obtained from a cDNA library prepared from tissue believed to possess the PR0213, PRO 1330, PRO 1449, PR0237. PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 mRNA and to express it at a detectable level Accordingly, human PR0213, human PRO 1330, human PRO 1449, human PR0237, human PR0324, human PR0351 , human PR0362, human PR0615, human PR0531 , human PR0538 human PR03664, human PR0618, human PR0772, human PRO703, human PR0792 or human PR0474 DNA can be conveniently obtained from a cDNA library prepared from human tissue, such as described in the Examples PR0213-, PRO1330-, PR01449-, PR0237-, PR0324-, PR0351-,
- Probes such as antibodies to the PR0213, PRO 1330, PROl 449. PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 oi PR0474 polypeptide, or oligonucleotides of at least about 20-80 bases
- Screening the cDNA or genomic library with the selected probe may be conducted using standard procedures, such as described in Sambrook etal, Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989).
- the oligonucleotide sequences selected as probes should be of sufficient length and sufficiently unambiguous that false positives are minimized.
- the oligonucleotide is preferably labeled such that it can be detected upon hybridization to DNA in the library being screened. Methods of labeling are well known in the art, and include the use of radiolabels like 32 P-labeled ATP, biotinylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringency, are provided in Sambrook et al., supra.
- Sequences identified in such library screening methods can be compared and aligned to other known sequences deposited and available in public databases such as GenBank or other private sequence databases. Sequence identity (at either the amino acid or nucleotide level) within defined regions of the molecule or across the full-length sequence can be determined using methods known in the art and as described herein.
- Nucleic acid having protein coding sequence may be obtained by screening selected cDNA or genomic libraries using the deduced amino acid sequence disclosed herein for the first time, and, if necessary, using conventional primer extension procedures as described in Sambrook et al., supra, to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA.
- Host cells are transfected or transformed with expression or cloning vectors described herein for PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences.
- the culture conditions such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology: a Practical Approach, M. Butler, ed. (IRL Press, 1991 ) and Sambrook et al, supra.
- Methods of eukaryotic cell transfection and prokaryotic cell transformation are known to the ordinarily skilled artisan, for example, CaCl 2 , CaP0 4 , liposome-mediated and electroporation.
- transformation is performed using standard techniques appropriate to such cells.
- the calcium treatment employing calcium chloride, as described in Sambrook et al., supra, or electroporation is generally used for prokaryotes.
- Infection with Agrobacterium tumefaciens is used for transformation of certain plant cells, as described by Shaw et al, Gene, 23:315 (1983) and WO 89/05859 published 29 June 1989.
- Suitable host cells for cloning or expressing the DNA in the vectors herein include prokaryote, yeast, or higher eukaryote cells
- Suitable prokaryotes include but are not limited to eubacte ⁇ a, such as Gram-negative or Gram-positive organisms, for example, Enterobacte ⁇ aceae such as E coli
- E coli strains are publicly available, such as E coli KI 2 strain MM294 (ATCC 31 ,446), E colt XI 776 (ATCC 31 ,537), E coli strain W31 10 (ATCC 27,325) and E coli strain K5 772 (ATCC 53,635)
- Other suitable prokaryotic host cells include Enterobacte ⁇ aceae such as Eschenchia, e g , E coli, Enterobactei , Erwima, Klebsiella, Proteus, Salmonella, e g Salmonella typhimurium, Set raha,
- K fiagihs (ATCC 12,424) K bulgartcus (ATCC 16,045), AT wicketamii (ATCC 24,178), K waltu (ATCC 56 500) K diosoplulat urn (ATCC 36,906, Vanden Berg etal , Bio/Technology, 8 135 (1990)), K thei ⁇ toleians.
- Methylotropic yeasts are suitable herein and include, but are not limited to, yeast capable of growth on methanol selected from the genera consisting of Hansenula Candida Kloeckeia, Ptchia Saccharonnces Torulopsis, and Rhodotot ula
- yeast capable of growth on methanol selected from the genera consisting of Hansenula Candida Kloeckeia, Ptchia Saccharonnces Torulopsis, and Rhodotot ula
- yeast capable of growth on methanol selected from the genera consisting of Hansenula Candida Kloeckeia, Ptchia Saccharonnces Torulopsis, and Rhodotot ula
- yeast capable of growth on methanol selected from the genera consisting of Hansenula Candida Kloeckeia, Ptchia Saccharonnces Torulopsis, and Rhodotot ula
- Rhodotot ula Rhodotot ula
- the nucleic acid (e g , cDNA or genomic DNA) encoding PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 may be inserted into a replicable vector for cloning (amplification of the DNA) or for expression Various vectors are publicly available The vector may, for example, be in the form of a plasmid, cosmid, viral particle, oi phage
- the appropriate nucleic acid sequence may be inserted into the vector by a variety of procedures In general, DNA is inserted into an appropriate restriction endonuclease s ⁇ te(s) using techniques known in the art
- Vector components generally include, but are not limited to one or more of a signal sequence an origin ot replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence Construction
- the PR0213, PRO 1330, PRO l 449, PR0237, PR0324 PR0351 , PR0362, PR0615, PR0531 , PR0538 PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 may be produced recombinantly not only directly but also as a fusion polypeptide with a heterologous polypeptide which may be a signal sequence or othei polypeptide having a specific cleavage site at the N terminus ot the mature protein or polypeptide
- the signal sequence may be a component of the vector, or it may be a part ot the PR021 -, PRO 1330 PRO 1449 PR0237-, PR0324-, PR0351 , PR0362-, PR061 , PR05 1 - PR0538 PR03664-, PR0618-, PR0772 PRO703-, PR0792- or PR0474 encoding DNA that is inserted into the vector
- the signal sequence may be a prok
- Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e g , ampicillin, neomycin, methotrexate, or tetracychne, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e g , the gene encoding D-alamne racemase for Bacilli
- suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the PR0213-, PRO1330-, PROl 449-, PR0237-, PR0324-, PR0351-, PR0362-, PR0615-, PR0531 -, PR0538-, PR03664-, PRO ⁇ l 8-, PR0772-, PRO703-, PR0792- or PR0474-encod ⁇ ng nucleic acid, such as DHFR or thymidine kinase
- An appropriate host cell when wild-type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al , Proc Natl Acad Sci USA, 77.4216 (1980)
- a suitable selection gene for use in yeast is the trp ⁇ gene present in the yeast plasmid YRp7 [Stinchcomb et al , Nature.
- the trp ⁇ gene provides a selection marker for a mutant strain ot yeast lacking the ability to grow in tryptophan, for example, ATCC No 44076 or PEP4-1 [Jones, Genetics, 85 12 (1977)]
- Expression and cloning vectors usually contain a promoter operably linked to the PR0213-, PRO1330-, PR01449-, PR0237-, PR0324-, PR0351 -, PR0362-, PR0615-, PR0531 -, PR0538-, PR03664-, PR0618-, PR0772-, PRO703-, PR0792- or PR0474-encod ⁇ ng nucleic acid sequence to direct mRNA synthesis
- Pi o oters recognized by a variety of potential host cells are well know n Promoters suitable for use with prokaryotic hosts include the ⁇ -lactamase and lactose promoter systems [Chang etal .
- Suitable promoting sequences toi use with yeast hosts include the promoters for 3- phosphoglycerate kinase [Hitzeman et al , J Biol Chem . 255 2073 ( 1980) j or other glycolytic enzymes [Hess et al J Ad ⁇ Enzyme Reg . 7 149 (1968), Holland, Biochemistry. ]7 4900 ( 1978)]. such as enolase.
- yeast promoters which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enz ⁇ mes associated with nitrogen metabolism, metallothionein, glyceraldehyde 3- phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization Suitable vectors and promoters for use in yeast expression are further described in EP 73,657
- PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published 5 July 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (S V40), from heterologous mammalian promoters, e g , the actin promoter or an immunoglobulin promoter, and from heat shock promoters, provided such promoters are compatible with the host cell systems
- viruses such as polyoma virus, fowlpo
- Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription
- Many enhancer sequences are now known from mammalian genes (globm, elastase, albumin, ⁇ -fetoprotem, and insulin)
- an enhancer from a eukaryotic cell virus examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers
- the enhancer include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers The enhance
- Expression vectors used in eukaryotic host cells will also contain sequences necessary for the termination ot transcription and for stabilizing the mRNA Such sequences are commonly available from the 5 and, occasionally 3 , untranslated regions of eukaryotic oi ⁇ iral DNAs or cDNAs These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding PR021 PRO l 330, PRO 1449, PR0237, PR0324, PR0351 , PR0362 PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474
- vectois and host cells suitable for adaptation to the synthesis ot PR0213 PRO 1330 PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 PR0538, PR03664, PR0618 PR0772 PRO703, PR0792 or PR0474 in recombinant vertebrate cell culture are described in Gething et al , Nature, 293 620-625 (1981 ). Mantei et al . Nature. 281 40-46 (1979) EP 1 17,060, and EP 1 17 058
- Gene amplification and/or expression may be measured in a sample directly for example by conventional Southern blotting, Northern blotting to quantitate the transcription ot mRNA [Thomas, Pi c Natl Acad Sci USA 225201-5205 ( 1980)], dot blotting (DNA analysis) or m situ hybridization, using an appropriately labeled probe based on the sequences provided herein
- antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA RNA hybrid duplexes or DNA-protein duplexes
- the antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected
- Gene expression alternatively, may be measured by immunological methods, such as lmmunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product Antibodies useful for
- PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 may be recovered from culture medium or from host cell lysates If membrane bound, it can be released from the membrane using a suitable detergent solution (e g , T ⁇ ton-X 100) or by enzymatic cleavage Cells employed in expression of PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents
- PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362 PR0615, PR0531 PR0538, PR03664, PRO ⁇ l 8, PR0772, PRO703, PR0792 or PR0474 from recombinant cell proteins or polypeptides The following procedures are exemplary ot suitable purification procedures by fractionation on an ion-exchange column, ethanol precipitation, reverse phase HPLC, chromatography on silica or on a cation-exchange resm such as DEAE, chromatofocusing, SDS-PAGE, ammonium sulfate precipitation, gel filtration using, for example, Sephadex G 75, protein A Sepharose columns to remove contaminants such as IgG, and metal chelating columns to bind epitope tagged forms ot the PR0213, PRO 1 30, PRO 1449, PR0237, PR0324 PR0351 , PR0362, PR0615, PR0531 , PR0538, PR
- PRQ35 PRQ362. PRQ615. PRQ531 PRQ538, PRQ3664, PRQ6I 8 PRQ772, PRO703, PRQ792 or PRQ474 Polypeptides in Tumor Tissues and Cell Lines
- the genome of prokaryotic and eukaryotic organisms is subjected to two seemingly conflicting requirements One is the preservation and propagation of DNA as the genetic information in its original form, to guarantee stable inheritance through multiple generations
- the adaptive mechanisms can include qualitative or quantitative modifications of the genetic material
- Qualitative modifications include DNA mutations, in which coding sequences are altered resulting in a structurally and/or functionally different protein
- Gene amplification is a quantitative modification, whereby the actual number of complete coding sequence, i e , a gene, increases, leading to an increased number of available templates for transcription, an increased number of translatable transcripts, and, ultimately, to an increased abundance of the protein encoded by the amplified gene
- the phenomenon of gene amplification and its underlying mechanisms have been investigated in vitio in several prokaryotic and eukaryotic culture systems
- the best-charactei lzed example of gene amplification involves the culture of eukaryotic cells in medium containing variable concenti
- Gene amplification is most commonly encountered in the development of resistance to cytotoxic drugs (antibiotics for bacteria and chemotherapeutic agents for eukaryotic cells) and neoplastic transformation Transformation of a eukaryotic cell as a spontaneous event or due to a vual oi chemical/environmental insult is typically associated with changes in the genetic material ot that cell
- cytotoxic drugs antibiotics for bacteria and chemotherapeutic agents for eukaryotic cells
- neoplastic transformation Transformation of a eukaryotic cell as a spontaneous event or due to a vual oi chemical/environmental insult is typically associated with changes in the genetic material ot that cell
- One of the most common genetic changes observed in human malignancies are mutations of the ⁇ 53 protein p53 controls the transition of cells from the stationary (Gl ) to the replicative (S) phase and prevents this transition in the presence of DNA damage
- Gl stationary
- S replicative
- one of the main consequences of disabling p53 mutations is the accumulation
- CGH comparative genomic hybridization
- such genes have been identified by quantitative PCR (S Gelmini et al , Chn Chem , 43 752 [1997]), by comparing DNA from a variety ot primary tumors, including bieast, lung, colon, prostate, brain, liver, kidney, pancreas, spleen, thy us, testis, ovary, uterus, etc , tumor, or tu oi cell lines, with pooled DNA from healthy donors Quantitative PCR w as perfoimed using a TaqMan instiument (ABI) Gene-specific p ⁇ meis and fluorogenic probes were designed based upon the coding sequences ot the DNAs
- Human lung carcinoma cell lines include A549 (SRCC768), Calu- 1 (SRCC769), Calu-6 (SRCC770), HI 57 (SRCC771 ), H441 (SRCC772) H460 (SRCC773), SKMES-1 (SRCC774), SW900 (SRCC775), H522 (SRCC832),and H810 (SRCC833), all available from ATCC
- Primary human lung tumor cells usually derive from adenocarcinomas, squamous cell carcinomas, large cell carcinomas, non-small cell carcinomas, small cell carcinomas, and broncho alveolar carcinomas, and include, for example, SRCC724 (adenocarcinoma, abbreviated as "AdenoCa")(LTl ), SRCC725 (squamous cell carcinoma, abbreviated as "SqCCa)(LTl a), SRCC726 (adenocarc ⁇ noma)(LT2), SRCC727 (adenocarc ⁇ nom
- SRCC891 (adenocarcinoma) (LT30), SRCC892 (squamous cell carcinoma) (LT31 ), SRCC894 (adenocarcinoma) (LT33)
- human lung tumors designated SRCC1 125 [HF-000631 ], SRCC1127 [HF-000641], SRCC1 129 [HF-000643], SRCC1 133 [HF-000840], SRCC1 135 [HF-000842], SRCC1227 [HF-001291], SRCC1229 [HF-001293], SRCC1230 [HF-001294], SRCC1231 [HF-001295], SRCC1232 [HF-001296], SRCC1233 [HF-001297], SRCC1235 [HF-001299], and SRCC1236 [HF-001300]
- Colon cancer cell lines include, for example, ATCC cell lines SW480 (adenocarcinoma, SRCC776), SW620 (lymph node metastasis of colon adenocarcinoma, SRCC777), Colo320 (carcinoma, SRCC778), HT29 (adenocarcinoma, SRCC779), HM7 (a high mucin producing variant of ATCC colon adenocarcinoma cell line, SRCC780, obtained fromDr Robert Warren, UCSF), CaWiDr (adenocarcinoma, SRCC781 ), HCT1 16 (carcinoma, SRCC782), SKCOl (adenocarcinoma, SRCC783), SW403 (adenocarcinoma, SRCC784), LS174T (carcinoma, SRCC785), Colo205 (carcinoma, SRCC828), HCT15 (carcinoma, SRCC829), HCC
- CT23 (adenocarcinoma. SRCC910), CT24 (adenocarcinoma. SRCC91 1 ), CT25 (adenocarcinoma, SRCC912), CT26 (adenocarcinoma, SRCC913), CT27 (adenocarcinoma, SRCC914),CT28 (adenocarcinoma, SRCC915), CT29 (adenocarcinoma, SRCC916), CT30 (adenocarcinoma, SRCC917), CT31 (adenocarcinoma. SRCC918), CT32 (adenocarcinoma.
- Human breast carcinoma cell lines include, tor example. HBL100 (SRCC759), MB435s (SRCC760), T47D (SRCC761 ), MB468(SRCC762), MB 175 (SRCC763), MB361 (SRCC764), BT20 (SRCC765), MCF7 (SRCC766), and SKBR3 (SRCC767), and human breast tumor center designated SRCC1057 [HF-000545] Also included are human breast tumors designated SRCC1094, SRCC1095, SRCC1096, SRCC1097, SRCC1098, SRCC1099, SRCC1 100, SRCC1 101 , and human breast met-lung-NS tumor designated SRCC893 [LT 32]
- Human kidney tumor centers include SRCC989 [HF-00061 1 ] and SRCC1014 [HF-000613]
- Human testis tumor center includes SRCC1001 [HF 000733] and testis tumor margin SRCC999 [HF-
- Human parathyroid tumor includes SRCC1002 [HF-000831 ] and SRCC1003 [HF-000832]
- gene amplification and/or gene expression in various tissues may be measured by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA (Thomas, Proc Natl Acad Sci USA.77 5201-5205 [1980]), dotblott ⁇ ng(DNA analys ⁇ s), or « situ hybridization, using an appropriately labeled probe, based on the sequences provided herein Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes
- Gene expression in various tissues may be measured by immunological methods, such as lmmunohistochemical staining of tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product
- Antibodies useful for lmmunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal Conveniently, the antibodies may be prepared against a native sequence PR0213, PRO 1330, PRO 1449, PR0237 PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to sequence PR0213 PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362 PR0615 PR0531 , PR0538, PR03664, PR06
- amplification ot a given gene is functionally relevant, then that gene should be amplified more than neighboring genomic regions which are not important for tumor survival To test this the gene can be mapped to a particular chromosome, e g , by radiation-hybrid analysis The amplification level is then determined at the location identified, and at the neighboring genomic region Selective or preferential amplification at the genomic region to which the gene has been mapped is consistent with the possibility that the gene amplification observed promotes tumor growth or survival Chromosome mapping includes both framework and epicenter mapping For further details see e g , Stewart et al , Genome Research. _ 1 422-433 (1997) H Antibody Binding Studies
- the results of the gene amplification study can be further verified by antibody binding studies, in which the ability of ant ⁇ -PR0213, anti-PROl 330, anti-PRO 1449, ant ⁇ -PR0237, ant ⁇ -PR0324, ant ⁇ -PR0351 , ant ⁇ -PR0362, ant ⁇ -PR0615, ant ⁇ -PR0531 , ant ⁇ -PR0538, ant ⁇ -PR03664, anti-PRO ⁇ l 8, ant ⁇ -PR0772, ant ⁇ -PRO703, anti PR0792 or ant ⁇ -PR0474 antibodies to inhibit the expression of PR0213, PROl 330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptides on tumor (cancer) cells is tested
- Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific, and heteroconju
- Antibody binding studies may be carried out in any known assay method, such as competitive binding assays, direct and indirect sandwich assays, and immunoprecipitation assays Zola, Monoclonal Antibodies A Manual of Techniques, pp 147-158 (CRC Press, Inc , 1987)
- Sandwich assays involve the use of two antibodies, each capable of binding to a different immunogenic portion, or epitope, of the protein to be detected
- the test sample analyte is bound by a first antibody which is immobilized on a solid support, and thereafter a second antibody binds to the analyte, thus forming an insoluble three-part complex
- the second antibody may itself be labeled with a detectable moiety (direct sandwich assays) or may be measured using an anti-immunoglobulin antibody that is labeled with a detectable moiety (indirect sandwich assay)
- sandwich assay is an ELISA assay, in which case the detectable moiety is an enzyme
- the tumor sample may be fresh or frozen or may be embedded in paraffin and fixed with a preservative such as formalin, for example
- Cell-based assays and animal models for tumors can be used to verify the findings of the gene amplification assay, and further understand the relationship between the genes identified herein and the development and pathogenesis of neoplastic cell growth
- the role ot gene products identified herein in the development and pathology of tumor or cancer can be tested by using primary tumor cells or cells lines that have been identified to amplify the genes herein Such cells include, for example, the breast colon and lung cancer cells and cell lines listed above
- Suitable cells include for example, stable tumor cells lines such as, the B 104 1- 1 cell line (stable NIH-3T3 cell line transfected with the neu protooncogene) and tas transfected NIH-3T3 cells, which can be transfected with the desired gene, and monitored for tumorogenic growth
- stable tumor cells lines such as, the B 104 1- 1 cell line (stable NIH-3T3 cell line transfected with the neu protooncogene) and tas transfected NIH-3T3 cells, which can be transfected with the desired gene, and monitored for tumorogenic growth
- Such transfected cell lines can then be used to test the ability of poly- or monoclonal antibodies or antibody compositions to inhibit tumorogenic cell growth by exerting cytostatic or cytotoxic activity on the growth of the transformed cells, or by mediating antibody-dependent cellular cytotoxicity (ADCC)
- ADCC antibody-dependent cellular cytotoxicity
- mice Animal models of tumors and cancers (e g , breast cancer, colon cancer, prostate cancer, lung cancer, etc ) include both non- recombinant and recombinant (transgenic) animals
- Non-recombinant animal models include, for example, rodent, e g , murine models
- Such models can be generated by introducing tumor cells into syngeneic mice using standard techniques, e g , subcutaneous injection, tail vein injection, spleen implantation, lntrape ⁇ toneal implantation, implantation under the renal capsule, or orthopin implantation, e g , colon cancer cells implanted in colonic tissue (See, e g , PCT publication No
- the cells introduced into such animals can be derived from known tumor/cancer cell lines, such as, any of the above-listed tumor cell lines, and, for example, the B 104- 1 -1 cell line (stable NIH-3T3 cell line transfected with the neu protooncogene), las transfected NIH 3T3 cells Caco-2 (ATCC HTB 37), a moderately well differentiated grade II human colon adenocarcinoma cell line HT-29 (ATCC HTB-38), or from tumors and cancers Samples of tumor or cancer cells can be obtained from patients undergoing surgery, using standard conditions involv ing freezing and storing in liquid nitrogen (Karmali et al Bi J Cancer, 48 689-696 [1983])
- Tumor cells can be introduced into animals such as nude mice, by a variety of procedures
- the subcutaneous (s c ) space in mice is very suitable for tumor implantation
- Tumors can be transplanted s c as solid blocks, as needle biopsies by use of a trochai , or as cell suspensions
- tumor tissue fragments of suitable size are introduced into the s c space
- Cell suspensions are freshly prepared from
- Tumor cells can also be injected as subdermal implants In this location, the inoculum is deposited between the lower part of the dermal connective tissue and the s c tissue Boven and Winograd (1991), supra
- Animal models of breast cancer can be generated, for example, by implanting rat neuroblastoma cells (from which the neu oncogen was initially isolated), or Hen-transformed NIH-3T3 cells into nude mice, essentially as described by Drebin et al , PNAS USA, 83 9129-9133 (1986)
- animal models of colon cancer can be generated by passaging colon cancer cells in animals, e g , nude mice, leading to the appearance of tumors in these animals
- An orthotopic transplant model of human colon cancer in nude mice has been described, for example, by Wang et al , Cancer Research, 54 4726-4728 ( 1994) and Too etal , Cancer Research. 55 681-684 (1995) This model is based on the so-called “METAMOUSE” sold by AntiCancer, Inc , (San Diego, California)
- Tumors that arise in animals can be removed and cultured in vitt o Cells from the in viti o cultures can then be passaged to animals Such tumors can serve as targets for further testing or drug screening Alternatively, the tumors resulting from the passage can be isolated and RNA from pre passage cells and cells isolated after one or more rounds of passage analyzed for differential expression of genes of interest Such passaging techniques can be performed with any known tumor or cancer cell lines
- Meth A, CMS4, CMS5, CMS21 , and WEHI-164 are chemically induced fibrosarcomas of BALB/c female mice (DeLeo et al , J Exp Med . 146 720 [1977]), which provide a highly controllable model system for studying the anti-tumor activities of various agents (Palladino et al , J Immunol , 138 4023-4032 [1987]) Briefly, tumor cells are propagated in vitro in cell culture Prior to injection into the animals, the cell lines are washed and suspended in buffer, at a cell density of about lOxl O 6 to 10xl0 7 cells/ml The animals are then infected subcutaneously with 10 to 100 ⁇ l of the cell suspension, allowing one to three weeks for a tumor to appear
- the Lewis lung (3LL) carcinoma of mice which is one of the most thoroughly studied experimental tumors, can be used as an investigational tumor model Efficacy in this tumor model has been correlated with beneficial effects m the treatment of human patients diagnosed with small cell carcinoma of the lung (SCCL)
- SCCL small cell carcinoma of the lung
- This tumor can be introduced in normal mice upon injection of tumor fragments from an affected mouse or of cells maintained in culture (Zupi et al , Br J Cancer, 41 suppl 4 309 [ 1980]), and evidence indicates that tumors can be started from injection of even a single cell and that a very high proportion of infected tumor cells survive For further information about this tumor model see, Zacharski, Haemostasis J6 300-320 [1986])
- One way of evaluating the efficacy of a test compound in an animal model on an implanted tumor is to measure the size of the tumor before and after treatment Traditionally, the size ot implanted tumors has been measured with a slide caliper in two or three dimensions The measure limited to
- Recombinant (transgenic) animal models can be engineered by introducing the coding portion of the genes identified herein into the genome of animals of interest, using standard techniques for producing transgenic animals
- Animals that can serve as a target for transgenic manipulation include, without limitation, mice, rats, rabbits, guinea pigs, sheep, goats, pigs, and non-human primates, e g , baboons, chimpanzees and monkeys
- Techniques known in the art to introduce a transgene into such animals include pronucleic microinjection (Hoppe and Wanger, U S Patent No 4,873,191), retrovirus-mediated gene transfer into germ lines (e g , Van der Putten et al , Proc Natl Acad Sci USA, 82 6148-615 [1985]), gene targeting in embryonic stem cells (Thompson etal , Cell, 56 313-321 [1989]), electroporation of embryos (Lo, Moi Cell Biol , 3 1803
- transgenic animals include those that carry the transgene only in part of their cells (“mosaic animals”).
- the transgene can be integrated either as a single transgene, or in concatamers, e g , head-to-head or head-to-tail tandems
- Selective introduction of a transgene into a particular cell type is also possible by following, for example, the technique of Lasko et al , Proc Natl Acad Sci USA, 89 6232- 636 (1992)
- the expression of the transgene in transgenic animals can be monitored by standard techniques For example, Southern blot analysis or PCR amplification can be used to verify the integration of the transgene The level of mRNA expression can then be analyzed using techniques such as in situ hybridization, Northern blot analysis, PCR, oi lmmunocytochemistry The animals are further examined for signs of tumor or cancer development
- "knock out" animals can be constructed which have a defective or altered gene encoding a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide identified herein, as a result of homologous recombination between the endogenous gene encoding the polypeptide and altered genomic DNA encoding the same polypeptide introduced into an embryonic cell of the animal
- cDNA encoding a PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664 PR0618 PR0772, PRO703, PR0792 or PR0474 polypeptide can be used to clone genomic DNA encoding that polypeptide in accordance with established techniques A portion of the genomic DNA encoding a
- Screening assays for drug candidates are designed to identity compounds that bind or complex with the polypeptides encoded by the genes identified herein, or otherwise interfere with the interaction of the encoded polypeptides with other cellular proteins
- Such screening assa> s w ill include assays amenable to high throughput screening of chemical libraries, making them particularly suitable toi identifying small molecule drug candidates
- Small molecules contemplated include synthetic organic or inorganic compounds including peptides preferably soluble peptides, (poly)pept ⁇ de immunoglobulin fusions, and m particular antibodies including without limitation poly and monoclonal antibodies and antibody fragments, single chain antibodies, anti-idiotypic antibodies, and chimeric or humanized versions of such antibodies or fragments as well as human antibodies and antibody fragments
- the assays can be performed in a variety of formats including protein-prote binding assays, biochemical screening assays, immunoassays and cell based assays, which are well characterized in the art
- the polypeptide encoded by the gene identified herein or the drug candidate is immobilized on a solid phase, e g , on a microtiter plate, by covalent or non-covalent attachments
- a solid phase e g
- an immobilized antibody e g , a monoclonal antibody, specific for the polypeptide to be immobilized can be used to anchor it to a solid surface
- the assay is performed by adding the non-immobilized component, which may be labeled by a detectable label, to the immobilized component, e g , the coated surface containing the anchored component
- the candidate compound interacts with but does not bind to a particular PR0213 , PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide encoded by a gene identified herein
- its interaction with that polypeptide can be assayed by methods well known for detecting protein-protein interactions
- Such assays include traditional approaches, such as, cross-linking, co-immunoprecipitation, and co-purification through gradients or chromatographic columns
- protein-protein interactions can be monitored by using a yeast-based genetic system described by Fields and co workers [Fields and Song, Nature, 340 245 246 (1989), Chien et ⁇ l , Proc Natl Acad Sci USA, 88 9578-9582 (1991 )] as disclosed by Chevray and Nathans, Proc Natl Acad Sci USA,
- the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide may be added to a cell along with the compound to be screened for a particular activity and the ability of the compound to inhibit the activity of interest in the presence of the PR0213, PROl 330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide indicates that the compound is an antagonist to the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide
- expi ession cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PRO-538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide and a cDNA libraiy created from this RNA is divided into pools and used to transtect COS cells or other cells that are not responsive to the PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664 PRO ⁇ l 8, PR0772 PRO703, PR0792 or PR0474 polypeptide Transfected cells that are grown on glass slides are exposed to labeled PR0213, PRO 1330, PR01449, PR0237 PR0324, PR0351 ,
- labeled PR0213, PROl 330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide can be photoaffimty-linked with cell membrane or extract preparations that express the receptor molecule
- Cross-linked material is resolved by PAGE and exposed to X ray film
- the labeled complex containing the receptor can be excised, resolved into peptide fragments, and subjected to protein micro-sequencing
- the amino acid sequence obtained from micro sequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA library to identify the gene encoding the putative receptor
- mammalian cells or a membrane preparation expressing the receptor would be incubated with labeled PR0213, PROl 330, PR01449, PR0237, PR0324,
- potential antagonists include an oligonucleotide that binds to the fusions of immunoglobulin with the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide, and, in particular, antibodies including, without limitation, poly- and monoclonal antibodies and antibody fragments, single chain antibodies, anti-idiotypic antibodies, and chimeric or humanized versions of such antibodies or fragments, as well as human antibodies and antibody fragments
- a potential antagonist may be a closely related protein, for example, a mutated form of the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide that
- PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide antagonist is an antisense RNA or DNA construct prepared using antisense technology, where, e g , an antisense RNA or DNA molecule acts to block directly the translation of mRNA by hybridizing to targeted mRNA and preventing protein translation
- Antisense technology can be used to control gene expression through t ⁇ ple-hehx formation oi antisense DNA or RNA, both of which methods are based on binding of a polynucleotide to DNA or RNA
- the 5' coding portion of the polynucleotide sequence which encodes the mature PR0213, PRO 1330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664 PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide herein, is used to design an antisense RNA
- RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into the PR0213, PROl 330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide (antisense - Okano, Neurochem , 56 560 (1991 ), Oh odeoxynucleotides as
- Potential antagonists include small molecules that bind to the active site, the receptor binding site, or growth factor or other relevant binding site of the PR0213, PROl 330, PRO 1449, PR0237, PR0324, PR0351 , PR0362, PRO ⁇ l 5, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide, thereby blocking the normal biological activity of the PR0213, PROl 330, PROl 449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PRO ⁇ l 8, PR0772, PRO703, PR0792or PR0474 polypeptide
- small molecules include, but are not limited to, small peptides or peptide-hke molecules, preferably soluble peptides, and synthetic non-peptidyl organic or inorganic compounds
- Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolvtic cleavage Specific ribozyme cleavage sites within a potential RNA target can be identified by known techniques For turthei details see, e g , Rossi, Current Biology, 4 469-471 (1994) and PCT publication No WO 97/335 ⁇ 1 (published
- Nucleic acid molecules in triple helix formation used to inhibit transcription should be single stranded and composed of deoxynucleotides
- the base composition of these oligonucleotides is designed such that it promotes triple helix formation via Hoogsteen base-pairing rules, which generally require sizeable stretches of punnes oi py ⁇ midmes on one strand of a duplex
- Hoogsteen base-pairing rules which generally require sizeable stretches of punnes oi py ⁇ midmes on one strand of a duplex
- compositions and Methods tor the Tieatment of Tumoi s include without limitation, antibodies, small organic and inorganic molecules, peptides, phosphopeptides antisense and ribozyme molecules, triple helix molecules etc that inhibit the expression and/or actn ltv of the target gene product
- antisense RNA and RNA molecules act to directly block the translation of mRNA by hybridizing to targeted mRNA and preventing protein translation
- oligodeoxy ⁇ bonucleotides derived from the translation initiation site, e g between about -10 and +10 positions of the target gene nucleotide sequence, are preferred
- Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolytic cleavage
- RNA target Specific ribozyme cleavage sites within a potential RNA target can be identified by known techniques For further details see, e g , Rossi, Current Biology, 4469-471 (1994), and PCT publication No WO 97/33551 (published September 18, 1997)
- Nucleic acid molecules in triple helix formation used to inhibit transcription should be single-stranded and composed of deoxynucleotides
- the base composition of these oligonucleotides is designed such that it promotes triple helix formation via Hoogsteen base pairing rules, which generally require sizeable stretches of punnes or py ⁇ midines on one strand of a duplex
- Hoogsteen base pairing rules which generally require sizeable stretches of punnes or py ⁇ midines on one strand of a duplex
- Some of the most promising drug candidates according to the present invention are antibodies and antibody fragments which may inhibit the production or the gene product of the amplified genes identified herein and/or reduce the activity of the gene products
- polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and, if desired, an adjuvant Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intrapentoneal injections
- the immunizing agent may include the PR0213, PRO 1330 PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772 PRO703, PR0792 oi PR0474 polypeptide or a fusion protein thereof It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin.
- adjuvants which may be employed include Freund's complete adjuvant and MPL TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate)
- the immunization protocol may be selected by one skilled in the art without undue experimentation
- anti PR0531 , ant ⁇ -PR0538, ant ⁇ -PR03664, ant ⁇ -PR0618, ant ⁇ -PR0772, ant ⁇ -PRO703, anti-PRO 792 or ant ⁇ -PR0474 antibodies may, alternatively, be monoclonal antibodies
- Monoclonal antibodies may be prepared using hybndoma methods, such as those described by Kohler and Milstein, Nature, 256 495 ( 1975) In a hybndoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent Alternatively, the lymphocytes may be immunized in viti o
- the immunizing agent will typically include the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 polypeptide, including fragments, or a fusion protein of such protein or a fragment thereof
- PBLs peripheral blood lymphocytes
- spleen cells or lymph node cells are used if non-human mammalian sources are desired
- the lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybndoma cell
- Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin Usually, rat
- Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium
- More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection (ATCC) Manassas, Virginia Human myeloma and mouse-human heteromyeloma cell lines also have been described foi the production of human monoclonal antibodies [Kozbor. J Immunol , 1 3 3001 ( 1984) Brodeurero/ . Monoclonal Antibody Production Techniques and Applications. Marcel Dekker. Inc . New Yoik. (1987) pp 51 -63]
- the culture medium in which the hybndoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against PR0213, PRO1330, PR01449 PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538 PRO3664, PRO618, PRO772, PRO703, PRO792o ⁇ PR0474 Pieterably the binding specificity of monoclonal antibodies produced by the hybndoma cells is determined by immunoprecipitation or b> an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme linked immunoabsorbent assay (ELISA) Such techniques and assays are known in the art
- the binding affinity of the monoclonal antibody can, 1 or example be determined by the Scatchard analysis of Munson and Pollard, Anal Biochem 107 220 ( 1980)
- the clones may be subcloned by limiting dilution procedures and grown by standard methods [Goding, supra] Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium Alternati ely, the hybndoma cells may be grown in vivo as ascites in a mammal
- the monoclonal antibodies secreted by the subclones may be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as tor example protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography
- the monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U S Patent No 4,816,567
- DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e g , by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies)
- the hybndoma cells of the invention serve as a preferred source of such DNA
- the DNA may be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells
- the DNA also may be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences [U S Patent No 4,816,567, Morrison
- antibodies may further comprise humanized antibodies or human antibodies
- Humanized forms of non-human (e g mu ⁇ ne) antibodies are chimeric immunoglobulins immunoglobulin chains or fi agments thereof (such as Fv, Fab, Fab', F(ab'), or other antigen-binding subsequences ot antibodies) which contain minimal sequence derived from non-human immunoglobulin Humanized antibodies include human immunoglobulins (recipient ant ⁇ bod>) in which residues from a complementary determining region (CDR) of the recipient are
- a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human
- These non- human amino acid residues are often referred to as "import' residues, which are typically taken from an "import" variable domain Humamzation can be essentially performed following the method of Winter and co-workers [Jones et al , Nature.
- humanized antibodies are chimeric antibodies (U S Patent No 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species
- humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies
- Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter. J Moi Biol , 227 381 ( 1991 ), Marks et al , J Moi Biol , 222 581 (1991 )] The techniques of Cole et al , and Boerner et al , are also available for the preparation of human monoclonal antibodies (Cole etal , Monoclonal Antibodies and Cancer Therapy, Alan R Liss, p 77 (1985) and Boerner etal , J Immunol , 147(1 ) 86-95 (1991)] Similarly, human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e g , mice in which the endogenous immunoglobulin genes have been partially or completely inactivated Upon challenge human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire This approach is described, for example, in U S
- ADPT Antibody Dependent Enzyme Mediated Prodrug Therapy
- the antibodies of the present invention may also be used in ADEPT by conjugating the antibody to a prodrug-activat g enzyme which converts a prodrug (e g , a peptidyl chemotherapeutic agent, see WO 81/01 145) to an active anti-cancer drug See, tor example, WO 88/07378 and U S Patent No 4,975,278
- a prodrug-activat g enzyme which converts a prodrug (e g , a peptidyl chemotherapeutic agent, see WO 81/01 145) to an active anti-cancer drug
- the enzyme component of the immunoconj ugate useful toi ADEPT includes any enzyme capable of acting on a prodrug in such as way so as to convert it into its moie activ e, cytotoxic form
- Enzymes that are useful in the method of this invention include, but are not limited to, glycosidase, glucose oxidase, human lysosyme, human glucuromdase, alkaline phosphatase useful for converting phosphate-containing prodrugs into free drugs, arylsultatase useful for converting sulfate containing prodrugs into tree drugs, cytosine deammase useful tor converting non toxic 5-fluorocytos ⁇ ne into the anti cancer drug 5-fluorourac ⁇ l, pioteases, such as serratia protease, thermolysin, subtihsin, carboxypeptidases (e s> , carboxypeptidase G2 and carboxypeptidase A) and cathepsins (such as cathepsins B and L), that are useful for converting peptide-contai ng prodrugs into free drugs, D-alanylcarboxypeptidases, useful for converting pro
- Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens
- one of the binding specificities is for the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 the other one is for any other antigen, and preferably for a cell surface protein or receptor or receptor subunit
- bispecific antibodies are known in the art Traditionally, the iecombinant production of bispecific antibodies is based on the co expression of two immunoglobulin heavy-chain/hght-chain pairs, where the two heavy chains have different specificities (Milstem and Cuello, Nature, 305 537-539 [ 1983]) Because of the random assortment of immunoglobulin heavy and light chains, these hybndomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure The purification of the correct molecule is usually accomplished by affinity chromatography steps Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al , EMBO J JO 3655-3659 (1991 ) Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences The fusion preferably is with an immunoglobulin heavy chain constant domain, comprising at least part of the hinge
- the interface between a pair ot antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture
- the preferred interface comprises at least a part of the CH3 region of an antibody constant domain
- one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e g , tyrosine or tryptophan)
- Compensatory "cavities" of identical or similar size to the large side cha ⁇ n(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e g , alanine or threonine)
- Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e g , F(ab') 2 bispecific antibodies) Techniques for generating bispecific antibodies from antibody fragments have been described in the literature For example, bispecific antibodies can be prepared using chemical linkage Brennan et al , Science, 229 81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab') 2 fragments These fragments are reduced in the presence of the dithiol complexing agent sodium arsemte to stabilize vicinal dithiols and prevent intermolecular disulfide formation The Fab' fragments generated are then converted to thiomtrobenzoate (TNB) derivatives One of the Fab'-TNB derivatives is then reconverted to the Fab'- thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody
- TAB thiomtrobenzoate
- Fab' fragments may be directly recovered from E coli and chemically coupled to form bispecific antibodies
- Shalaby et al , J Exp Med , 175 217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab') 2 molecule
- Each Fab' fragment was separately secreted from E coli and subjected to directed chemical coupling in vitw to form the bispecific antibody
- the bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets
- bispecific antibodies have been produced using leucine zippers Kostelny et al , J Immunol . 148(5) 1547- 1553 (1992)
- the leucine zipper peptides from the Fos and Jun proteins were linked to the Fab portions of two different antibodies by gene fusion
- the antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers
- This method can also be utilized for the production of antibody homodimers
- the "diabody ' technology described by Holhnger et al , Proc Natl Acad Sci USA.90 6444-6448 ( 1993) has pi ovided an alternative mechanism for making bispecific antibody fragments
- the fragments comprise a heavy-chain variable domain (V H ) connected to a light-chain variable domain (V L ) by a linker which is too short to allow pairing between the two domains on the same chain According
- Antibodies with more than two valencies are contemplated
- trispecif ic antibodies can be prepared Tutt et al , J Immunol . 147 60 ( 1991 )
- Exemplary bispecific antibodies may bind to two different epitopes on a given polypeptide herein
- an anti-polypeptide arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e g , CD2, CD3, CD28, or B7), or Fc receptors for IgG (Fc ⁇ R), such as Fc ⁇ RI (CD64), Fc ⁇ RII (CD32) and Fc ⁇ RIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular polypeptide
- Bispecific antibodies may also be used to localize cytotoxic agents to cells which express a particular polypeptide
- These antibodies possess a polypeptide binding arm and an arm which binds a cytotoxic agent or a radionuclide
- Heteroco ugate Antibodies are composed of two covalently joined antibodies Such antibodies have, for example, been proposed to target immune system cells to unwanted cells [U S Patent No 4,676,980], and for treatment of HIV infection [WO 91/00360, WO 92/200373, EP 03089] It is contemplated that the antibodies may be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosshnking agents For example, immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond Examples of suitable reagents for this purpose include lminothiolate and methyl-4- mercaptobuty ⁇ midate and those disclosed, for example, in U S Patent No 4,676,980
- cyste e res ⁇ due(s) may be introduced in the Fc region, thereby allowing interchain disulfide bond formation in this region
- the homodimenc antibody thus generated may have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC) See Caron et al , J Exp Med , 176 1191-1 195 ( 1992) and Shopes, J Immunol , 148 2918-2922 ( 1992)
- Homodimenc antibodies with enhanced anti-tumor acti v ⁇ t> may also be prepared using heterobifunctional cross-linkers as described in Wolff etal , Cancer Research, 53 2560 2565 (1993)
- an antibody can be engineered which has dual Fc regions and may thereby have enhanced complement lysis and ADCC capabilities See, Ste enson et al , Anti-Cancer Drug
- the invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e g , an enzymatically activ e toxin ot bacterial, fungal, plant oi animal origin, or fragments thereof, or a small molecule toxin), or a radioactive isotope e , a radioconjugate)
- a cytotoxic agent such as a chemotherapeutic agent, toxin (e g , an enzymatically activ e toxin ot bacterial, fungal, plant oi animal origin, or fragments thereof, or a small molecule toxin)
- toxin e g , an enzymatically activ e toxin ot bacterial, fungal, plant oi animal origin, or fragments thereof, or a small molecule toxin
- radioactive isotope e a radioconjugate
- Enzymatically active protein toxins and fragments thereof which can be used include diphtheria A chain, nonbmding active fragments of diphtheria toxin, cholera toxin, botuhnus toxin exotoxin A chain (from Pseudomonas aei uginosa), ncin A chain, ab ⁇ n A chain, modeccin A chain alpha-sarcin Aleui ites foidu proteins, dianthin proteins, Plntolaca amencana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin crot , sapaonana officinahs inhibitor, gelonin, saponn, mitogelhn, restnctocm, phenomycin, enomycin and the tncothecenes
- Small molecule toxins include, for example, cahcheamicins, maytansinoids, palytoxin and CC 1065 A variety of radionuch
- Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein coupling agents such as N-succm ⁇ m ⁇ dyl-3-(2-py ⁇ dyld ⁇ th ⁇ ol) propionate (SPDP), lminothiolane (IT), bifunctional derivatives of lmidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as b ⁇ s-(p-d ⁇ azon ⁇ umbenzoyl)-ethylened ⁇ am ⁇ ne), diisocyanates (such as tolyene 2,6-d ⁇ socyanate), and bis- active fluorine compounds (such as l,5-d ⁇ fluoro-2,4-d ⁇ n ⁇ trobenzen
- Immunoliposomes The antibodies disclosed herein may also be formulated as immunoliposomes Liposomes containing the antibody are prepared by methods known the art, such as described in Epstein etal , Proc Natl Acad Sci USA, 82 3688 (1985), Hwang et al , Proc Natl Acad Sci USA, 724030 (1980), and U S Patent Nos 4485,045 and 4,544,545 Liposomes with enhanced circulation time are disclosed in U S Patent No 5,01 ,556
- Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphaudylchohne, cholesterol and PEG-denvatized phosphatidylethanolamine (PEG PE) Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al J Biol Chem .
- a chemotherapeutic agent such as Doxorubicin is optionally contained within the hposome See, Gabizon efa/ , J National Cancer Inst 81(19) 1484 (1989)
- Antibodies specifically binding the product of an amplified gene identified herein, as well as othei molecules identified by the screening assays disclosed heieinbefore, can be administered tor the tieatment of tumors including cancers, in the form ot pharmaceutical compositions If the protein encoded by the amplified gene is mtracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred However, lipofections or liposomes can also be used to deliver the antibod) or an antibody fragment into cells Where antibody fragments are used, the smallest inhibitory fragment which specifically binds to the binding domain of the target protein is preferred For example, based upon the variable region sequences of an antibody, peptide molecules can be designed which retain the ability to bind the target protein sequence Such peptides can be synthesized chemically and/or produced by recombinant DNA technology (see, e g , Marasco et l , Proc Natl Acad Sci USA, 90 7889-7893 [1993])
- Therapeutic formulations ot the antibody are prepared for storage by mixing the antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences. 16th edition, Osol, A ed [1980]), in the form of lyophilized formulations or aqueous solutions
- Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids, antioxidants including ascorbic acid and methionine, preservatives (such as octadecyldimethylbenzyl ammonium chloride, hexamethomum chloride, benzalkomum chloride, benzethomum chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and /
- compositions herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other Alternatively, or in addition, the composition may comprise a cytotoxic agent, cytokine or growth inhibitor) agent Such molecules are suitably present in combination in amounts that are effective tor the purpose intended
- the active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by mterfacial polymerization, for example, hydroxymethylcellulose or gelatin microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal diug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano particles and nanocapsules) or in macroemulsions Such techniques are disclosed in Remington s Pharmaceutical Sciences, 16th edition, Osol A ed (1980)
- the formulations to be used for /// vivo administration must be sterile This is readily accomplished by filtration through sterile filtration membranes
- Sustained-release preparations may be prepared Suitable examples ot sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e g , films or microcapsules
- ot sustained-release matrices include polyesters hydrogels (for example, poly(2 hydroxyethyl-methacrylate) or poly(v ⁇ nylalcohol)), polylactides (U S Pat No 3,773,919), copolymers of L glutamic acid and ethyl L glutamate, non degradable ethylene vinyl acetate degradable lactic acid glycolic acid copolymers such as the LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycohc acid copolymer and leuprohde acetate), and poly-D-(-)-3-hydroxybuty ⁇ c acid While polymers such as ethylene-vinyl acetate and lactic acid
- the antibodies and other anti -tumor compounds of the present invention may be used to treat various conditions, including those characterized by overexpression and/or activation of the amplified genes identified herein
- Exemplary conditions or disorders to be treated with such antibodies and other compounds include benign or malignant tumors (e g , renal, liver, kidney, bladder, breast, gastric, ovarian, coloiectal, prostate, pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas, ghoblastomas, and various head and neck tumors), leukemias and lymphoid malignancies, other disorders such as neuronal, ghal, astrocytal, hypothalamic and other glandular, macrophagal, epithelial, stromal and blastocoehc disorders, and inflammatory, angiogemc and lmmunologic disorders
- the anti-t tumors e g , renal, liver, kidney, bladder, breast, gastric, ovarian, coloiec
- chemotherapeutic agents may be administered to the patient Preparation and dosing schedules for such chemotherapeutic agents may be used according to manufacturers' instructions or as determined empirically by the skilled practitioner Preparation and dosing schedules for such chemotherapy are also described in Chemotherapy Service Ed , M C Perry, Williams &W ⁇ lkms, Baltimore, MD (1992)
- the chemotherapeutic agent may precede or follow administration of the anti-tumor agent, e g , antibody, or may be given simultaneously therewith
- the antibody may be combined with an anti-oestrogen compound such as tamoxifen or an anti-progesterone such as onap ⁇ stone (see. EP 616812) in dosages known for such molecules
- the antibodies herein are co-administered with a growth inhibitory agent
- the growth inhibitory agent may be administered first, followed by an antibody of the present invention
- simultaneous administration or administration of the antibody of the present invention first is also contemplated Suitable dosages for the growth inhibitory agent are those presently used and may be lowered due to the combined action (synergy) of the growth inhibitory agent and the antibody herein
- an anti-tumor agent e g , an antibody herein will depend on the type of disease to be treated, as defined above, the severity and course of the disease whether the agent is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the agent, and the discretion of the attending physician
- the agent is suitably administered to the patient at one time or over a series of treatments
- ⁇ g/kg to 15 mg/kg (e g , 0 1 -20 mg/kg) of antibody is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion
- a typical daily dosage might range from about 1 ⁇ g/kg to 100 mg/kg or more, depending on the factors mentioned above
- the treatment is sustained until a desired suppression of disease symptoms occurs
- other dosage regimens may be useful The progress of this therapy is easily monitored by conventional techniques and assays
- an article of manufacture containing materials useful for the diagnosis or treatment of the disorders described above comprises a container and a label Suitable containers include, for example, bottles, vials, syringes, and test tubes
- the containers may be formed from a variety of materials such as glass or plastic
- the container holds a composition which is effective for diagnosing or treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic inaction needle)
- the active agent in the composition is usually an anti-tumor agent capable of interfering with the activitv of a gene product identified herein, e g , an antibody
- the label on or associated with, the container indicates that the composition is used for diagnosing or treating the condition of choice
- the article of manufacture may turthei comprise a second container comprising a pharmaceutically-acceptable buffer, such as phosphate-buffered saline Ringer's solution and dext
- antibodies directed against the piotem products of genes amplified in tumor cells can be used as tumor diagnostics or prognostics
- antibodies, including antibody fragments can be used to qualitatively or quantitatively detect the expression of proteins encoded by the amplified genes ("marker gene products")
- the antibody preferably is equipped with a detectable, e g , fluorescent label, and binding can be monitored by light microscopy, flow cytometry, fluo ⁇ metry, or other techniques known in the art These techniques are particularly suitable, if the amplified gene encodes a cell surface protein, e g , a growth factor Such binding assays are performed essentially as described in section 5 above
- In situ detection of antibody binding to the marker gene products can be performed, for example, by immunofluorescence or immunoelectron microscopy
- a histological specimen is removed from the patient, and a labeled antibody is applied to it, preferably by overlaying the antibody on a biological sample
- This procedure also allows for determining the distribution of the marker gene product in the tissue examined It will be apparent for those skilled in the art that a wide variety of histological methods are readily available for in situ detection
- the present invention uses standard piocedures of recombinant DNA technolog) such as those described hereinabove and in the following textbooks Sambrook et al , Molecular Cloning A Laboratory Manual. Cold Spring Harbor Press N Y , 1989, Ausubel etal . Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience N Y , 1989, Innis eta! , PCR Protocols A Guide to Methods and Applications. Academic Press. Inc , N Y , 1990, Harlow et al . Antibodies A Laboratory Manual Cold Spring Harbor Press. Cold Spring Harbor. 1988 Gait, Oligonucleotide Synthesis, IRL Press, Oxford, 1984, R I Fieshney, Animal Cell Culture, 1987. Cohgan et al . Current Protocols in Immunology, 1991 EXAMPLE 1
- ECD extracellular domain sequences
- EST expressed sequence tag
- DNA28735 A consensus DNA sequence was assembled relative to other Incyte EST sequences using phrap This consensus sequence is herein designated DNA28735 Based on the DNA28735 consensus sequence, oligonucleotides were synthesized 1 ) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of PR0213, PRO1330 and PR01449 full-length coding sequences Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length The probe sequences are typically 40-55 bp in length In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1 - 1 5kbp In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al , Current Protocols in Molecular Biology, with the PCR
- oligonucleotide hybridization probe was constructed from the consensus DNA28735 sequence which had the following nucleotide sequence hybridization probe
- RNA for construction of the cDNA libraries was isolated from human fetal lung tissue
- the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commeicially available reagents such as those from Invitrogen, San Diego, CA
- the cDNA was primed with ohgo dT containing a Notl site, linked with blunt to Sail hemikinased adaptors, cleaved with Notl, sized appiop ⁇ ately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD, pRK5B is a precursor of pRK5D that does not contain the St ii site, see, Holmes et al . Science, 253 1278- 1280 ( 1 91 )) in the unique Xhol and Notl sites
- DNA30943-1 163 (SEQ ID NO 3), DNA64907-1 163 (SEQ ID NO 5) and DNA64908-1 163 (SEQ ID NO 7) contain single open reading frames with apparent translational initiation sites at nucleotide positions 399-401 , 488-490 and 326-328, respectively, and ending at the stop codons at nucleotide positions 1218-1220, 1307-1309 and 1145-1 147, respectively ( Figures 3, 5 and 7, respectively)
- the predicted polypeptide precursors are 273, 273 and 273 amino acids long, respectively ( Figures 4, 6 and 8, respectively)
- Analysis ot the full-length PR0213, PRO 1330 and PRO 1449 sequences shown in Figure 4 (SEQ ID NO 4), Figure 6 (SEQ ID NO 6) and Figure 8 (SEQ ID NO 8), respectively evidences the presence of the following a signal peptide from about amino acid 1 to about amino acid 19, cAMP- and cGMP-dependent protein kinase phosphorylation sites from about amino acid
- EXAMPLE 2 Isolation of cDNA Clones Encoding PRQ237
- the extracellular domain (ECD) sequences (including the secretion signal, if any) of about 950 known secreted proteins from the Swiss-Prot public protein database were used to search expressed sequence tag (EST ) databases
- the EST databases included public EST databases (e g , GenBank) and a proprietary EST DNA database (LIFESEQ ® , Incyte Pharmaceuticals, Palo Alto, CA)
- the search was performed using the computei program BLAST or BLAST2 ( Altshul et al , Methods in Enzymoiogy.266 460-480 ( 1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap'
- DNA30905 Based on the DNA30905 consensus sequence oligonucleotides were synthesized 1 ) to identify by PCR a cDNA library that contained the sequence ot interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0237
- Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product ot about 100-1000 bp in length
- the probe sequences are typically 40-55 bp in length
- additional oligonucleotides are synthesized when the consensus sequence is greater than about 1 -1 5 kbp
- DNA from the libraries was screened by PCR amplification, as per Ausubel et al , Current Protocols in Molecular Biology with the PCR primer pair A positive library was then used to isolate clones en
- PCR primers (forward and reverse) were synthesized forward PCR primer
- a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30905 sequence which had the following nucleotide sequence hybridization probe 5'-GCCTCTTTGTCAACGTTGCCAGTACCTCTAACCCATTCCTCAGTCGCCTC 3' (SEQ ID NO 39)
- DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above A positive library was then used to isolate clones encoding the PR0237 gene using the probe oligonucleotide and one ot the PCR primers
- RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (LIB 153)
- the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA
- the cDNA was primed with ohgo dT containing a Notl site, linked with blunt to Sail hemikmased adaptois, cleaved with Notl, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD, pRK5B is a precursor of pRK5D that does not contain the Sfil site, see, Holmes et al , Science, 253 1278-1280 (1991)) in the unique Xhol and Notl sites
- DNA sequencing of the clones isolated as described above gave the full length DNA sequence tor PR0237
- EXAMPLE 3 Isolation of cDNA Clones Encoding a Human PRQ324
- the extracellular domain (ECD) sequences (including the secretion signal, if any) of from about 950 known secreted proteins from the Swiss-Prot public protein database were used to search expressed sequence tag
- EST databases included public EST databases (e g , GenBank) and a proprietary EST DNA database (LIFESEQ ® , Incyte Pharmaceuticals, Palo Alto, CA) The search was performed using the computer program BLAST or BLAST2 (Altshul etal , Methods in Enzymology. 266 460-480 (1996)) as a comparison of the
- DNA34347 Based on the DNA34347 consensus sequence, oligonucleotides were synthesized 1 ) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0324 Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length The probe sequences are typically 40-55 bp in length In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1 -
- PCR primers (forward and reverse) were synthesized forward PCR primer 1
- oligonucleotide hybridization probe was constructed from the consensus DNA34347 sequence which had the following nucleotide sequence hybridization probe
- RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB6)
- the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA
- the cDNA was primed with ohgo dT containing a Notl site, linked with blunt to Sail hemikinased adaptors, cleaved with Notl, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD, pRK5B is a precursor of pRK5D that does not contain the Sfil site, see, Holmes et al , Science, 253 1278- 1280 ( 1991 )) in the unique Xhol and Notl sites
- DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0324
- DNA36343 1310 [herein designated as DNA36343 1310] (SEQ ID NO 9) and the derived PR0324 protein sequence (SEQ ID NO 10)
- DNA36343-1310 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 144- 146 and ending at the stop codon at nucleotide positions 101 1-1013 ( Figure 9, SEQ ID NO 9)
- the predicted polypeptide precursor is 289 amino acids long ( Figure 10, SEQ ID NO 10)
- the full-length PR0324 protein shown in Figure 10 has an estimated molecular weight of about 32,268 daltons and a pi of about 9 21
- Analysis of the particular PR0324 polypeptide sequence shown in Figure 10 evidence the presence of the following a signal peptide from about amino acid 1 to about amino acid 31 , a transmembrane domain from about amino acid 136 to about amino acid 157, a tyrosine kinase phosphorylation site from about ammo acid 106 to about amino acid 114, and regions that
- oligonucleotides were synthesized 1 ) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for a PR0351
- Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length
- the probe sequences are typically 40-55 bp in length
- additional oligonucleotides are synthesized when the consensus sequence is greater than about 1 -1 5 kbp
- DNA from the libraries was screened by PCR amplification, as per Ausubel etal , Current Protocols in Molecular Biology, with the PCR primer pair A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs
- a synthetic oligonucleotide hybridization probe was constructed from DNA35950 which had the following nucleotide sequence hybridization probe 5'-GGCTGGCATCATCAGCTTTGCATCAAGCTGTGCCCAGGAGGACGC-3' (SEQ ID NO 48)
- DNA from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above A positive library was then used to isolate clones encoding the PR0351 gene using the probe oligonucleotide and one of the PCR primers
- RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB230)
- the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen. San Diego CA
- the cDN A was primed with ohgo dT containing a Notl site, linked with blunt to Sail hemikinased adaptors, cleaved with Notl, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vectoi (such as pRKB or pRKD, pRK5B is a precursor of pRK5D that does not contain the Sfil site, see, Holmes et al , Science. 253 1278- 1280 ( 1991 )) in the unique Xhol and Notl sites
- DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0351
- DNA40571 -1315 [herein designated as DNA40571 -1315] (SEQ ID NO 1 1 ) and the derived PR0351 protein sequence (SEQ ID NO 12)
- DNA40571 - 1315 contains two open reading frames with an apparent translational initiation site at nucleotide positions 189- 191 and a second open reading frame beginning at nucleotide 470 with the two open reading frames ending at the stop codons at nucleotide positions 363-365 and 2009 201 1 , respectivel) ( Figure 1 1 )
- the predicted polypeptide precursor is 571 amino acids long ( Figure 12)
- Important regions of the amino acid sequence of PR0351 include the signal peptide (amino acid residues 1 to about 15), regions having sequence similai lty to serine proteases of the trypsin family (i e , amino acid residues from about 79 to about 96, from about 343 to about 360 and from about 237 to about 248), two N-glycosylation sites (; e , amino acid residues from about 37 to about 41 and from about 564
- EXAMPLE 5 Isolation of cDNA Clones Encoding PRQ362
- the extracellular domain (ECD) sequences (including the secretion signal, if any) of from about 950 known secreted proteins from the Swiss-Prot public protein database were used to search expressed sequence tag (EST) databases
- the EST databases included public EST databases (e g , GenBank) and a proprietary EST DNA database (LIFESEQ ® , Incyte Pharmaceuticals, Palo Alto, CA)
- the search was performed using the computer program BLAST or BLAST2 (Altshul etal , Methods in Enzymology, 266 460-480 ( 1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap” (Phil Green, University of Washington, Seattle, Washington)
- DNA42257 Based on the DNA42257 consensus sequence, oligonucleotides were synthesized 1 ) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0362
- Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100- 1000 bp in length The probe sequences are typically 40-55 bp in length
- additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1 5 kbp
- DN A from the libraries was screened by PCR amplification, as per Ausubel et al , Current Protocols in Moleculai Biology, with the PCR primer pair A positive library was then used to isolate clones
- PCR primers (forward and reverse) were synthesized forward PCR primer 1
- RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (LIB 153)
- the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA The cDNA was primed with oligo dT containing a Notl site, linked with blunt to Sail hemikinased adaptors, cleaved with Notl, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD, pRK5B is a precursor of pRK
- DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0362 [herein designated as DNA45416-1251 ] (SEQ ID NO 13) and the derived PR0362 protein sequence (SEQ ID NO 14) The entire nucleotide sequence of DNA45416-1251 is shown in Figure 13 (SEQ ID NO 13) Clone
- DNA45416-1251 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 1 19-121 and ending at the stop codon at nucleotide positions 1082-1084 (Figure 13)
- the predicted polypeptide precursor is 321 amino acids long ( Figure 14, SEQ ID NO 14)
- the full-length PR0362 (UNQ317) protein shown in Figure 14 has an estimated molecular weight of about 35,544 daltons and a pi of about 8 51
- Analysis of the full-length PR0362 polypeptide as shown in Figure 14 evidences the presence of the following a signal sequence from about amino acid 1 to about amino acid 19, a transmembrane domain from about amino acid 281 to about amino acid 300, a glycosaminoglycan attachment site from about amino acid 149 to about amino acid 153, a cAMP and cGMP-dependent protein kinase phoshorylation site from about amino acid 308 to about ammo acid 312, and N-my ⁇ stoylation sites from
- EXAMPLE 6 Isolation of cDNA Clones Encoding Human PRQ615
- the extracellular domain (ECD) sequences (including the secretion signal, if any) of from about 950 known secreted proteins from the Swiss-Prot public protein database were used to search expressed sequence tag (EST) databases
- the EST databases included public EST databases (e c , GenBank) and a proprietary EST DNA database (LIFESEQ*, Incyte Pharmaceuticals, Palo Alto C ⁇ )
- the search was performed using the computei program BLAST or BLAST2 (Altshul et al , Methods in Enzvmology, 266 460-480 ( 1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program 'phrap' (Phil Green, University of Washington,
- oligonucleotide hybridization probe was constructed from the consensus DNA42240 sequence which had the following nucleotide sequence hybridization probe
- DNA from the libia ⁇ es was screened by PCR amplification with one of the PCR primer pairs identified above A positive library was then used to isolate clones encoding the PR0615 gene using the probe oligonucleotide and one of the PCR primers RNA for construction of the cDNA libraries was isolated f I om human bone marrow tissue (LIB255)
- the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA The cDNA was primed with ohgo dT containing a Notl site, linked with blunt to Sail hemikinased adaptors, cleaved with Notl.
- a suitable cloning vector such as pRKB or pRKD, pRK5B is a precursor of pRK5D that does not contain the Sfil site, vee, Holmes et al . Science 253 1278- 1280 ( 1991 )) in the unique Xhol and Notl sites
- DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0615 [herein designated as DNA48304-1 23] (SEQ ID NO 15) and the derived PR0615 protein sequence (SEQ ID NO 15)
- EXAMPLE 7 Isolation of cDNA Clones Encoding PRQ531 An ECD database was searched and an expressed sequence tag (EST) from LIFESEQ ® , Incyte Pharmaceuticals, Palo Alto, CA was identified This EST was identified as fragment number 1810051 which showed homology to protocadhenn 3 Based on this sequence, a search was performed using the computer program BLAST or BLAST2 (Altshul et al , Methods in Enzymology, 266 460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Washington) A consensus DNA sequence was assembled relative to other EST sequences using repeated cycles of
- oligonucleotides were synthesized 1 ) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PR0531
- Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length
- the piobe sequences are typically 40-55 bp in length
- additional oligonucleotides are synthesized when the consensus sequence is greater than about 1 -1 5 kbp
- DNA from the libraries was screened by PCR amplification, as per Ausubel etal , Current Protocols in Molecular Biology, with the PCR p ⁇ mei pair A positive library was then used to isolate clones encoding the gene ot interest using the probe oligonucleotide and one of the p ⁇
- a pair of PCR primers (forward and reverse) were synthesized forward PCR primer
- a synthetic oligonucleotide hybridization probe was constructed from the consensus sequence which had the following nucleotide sequence hybridization probe 5'-TTAGTTGCTCCATTCAGGAGGATCTACCCTTCCTCCTGAAATCCGCGGAA-3' (SEQ ID NO 61 )
- DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above A positive hbiary was then used to isolate clones encoding the PR0531 gene using the probe oligonucleotide and one of the PCR primers
- RNA for construction of the cDNA libraries was isolated from human fetal brain tissue (LIB 153)
- the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA
- the cDNA was primed with ohgo dT containing a Notl site, linked with blunt to Sail hemikinased adaptors, cleaved with Notl, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD , pRK5B is a precursor of pRK5D that does not contain the Sfil site, see, Holmes et al , Science, 253 1278- 1280 ( 1991 )) in the unique Xhol and Notl sites
- DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PR0531 [herein designated as DNA48314-1320] (SEQ ID NO 17) and the derived PR0531 protein sequence (SEQ ID NO 18)
- a cadhe ⁇ n extiacellular repeated domain signature is found at about amino acids 122-133, 231 -242, 336-347, 439-450 and 549-560.
- an ATP/GTP-binding site motif A (P-loop) is found at about amino acids 285-293 of SEQ ID NO 18, N-glycosylation sites are found at least at about amino acids 567-571 , 786-790, 418-422 and 436-440 of SEQ ID NO 18
- the signal peptide is at about amino acids 1 -26, and the transmembrane domain is at about amino acids 685-712 ot SEQ ID NO 18
- Alto, CA was searched foi homology to the murine GFR 3 nucleotide sequence and the EST sequence
- INC3574209 was identified and found to have 61 % sequence identity in the aligned region between the two sequences The following primers were created in order to screen tor the corresponding full length cDNAs newa3 F
- DNA from the libraries referenced below was screened by PCR amplification, as per Ausubel et al , Current Protocols in Molecular Biology (1995), with the PCR primer pair A strong PCR product was identified in all libraries analyzed (fetal lung, fetal kidney and placenta)
- a human fetal lung pRK5 vector library was selected and enriched for positive cDNA clones by extension of single stranded DNA from plasmid libraries grown in dug-/bung- hosts using the newa3 R primer RNA for construction of the cDN A libraries was isolated from human fetal lung tissue
- the cDNA library used to isolate the cDNA clones was constructed by standard methods using commercially available reagents (e g , Invitrogen, San Diego, CA, Clontech, etc )
- the cDNA was primed with oligo dT containing a Notl site, linked with blunt to Sail hemikinased adaptors, cleaved with Notl, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (pRKB or pRKD, pRK5B is a precursor of p
- DNA48613-1268 SEQ ID NO 19
- DNA48614-1268 SEQ ID NO 21
- Amino acid sequence analysis of DNA48613-1268 revealed a PR0538 polypeptide (SEQ ID NO 20) having a 400 amino acid reading frame sequence with a predicted 26 residue long N-terminal signal peptide
- the predicted mature protein is 374 amino acids long, with a calculated molecular weight of appioximately 41 kDa
- EXAMPLE 9 Isolation of cDNA Clones Encoding Human PRQ618
- the extracellular domain (ECD) sequences (including the secretion signal, if any) of from about 950 known secreted proteins from the Swiss-Prot public protein database were used to search expressed sequence tag (EST) databases
- the EST databases included public EST databases (e g , GenBank) and a proprietary EST DNA database (LIFESEQ ® , Incyte Pharmaceuticals, Palo Alto, CA) The search was pei formed using the computer program BLAST or BLAST2 (Altshul et al .
- DNA35597 (SEQ ID NO 25) was extended using repeated cycles of BLAST and phrap to extend the sequence as far as possible using Incyte and Genentech proprietary EST sequences The extended assembly sequence was used to generate the consensus nucleotide sequence designated herein as DNA43335, which was used to derive the final full length sequence for DNA49152- 1324 (SEQ ID NO 23)
- the sequence DNA35597 is an EST proprietary to Genentech Based on DNA35597, oligonucleotides were synthesized 1 ) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the PR0618 full-length coding sequence
- Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100- 1000 bp in length
- the probe sequences are typically 40-55 bp in length
- additional oligonucleotides are synthesized when the consensus sequence
- DNA from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above A positive library was then used to isolate full length clones encoding the PR0618 gene using the second probe oligonucleotide and one of the second set of PCR primers RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB229)
- the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA The cDNA was primed with ohgo dT containing a Notl site, linked with blunt to Sail hemikinased adaptors, cleaved with Notl.
- a suitable cloning vector such as pRKB or pRKD, pRK5B is a precursor of pRK5D that does not contain the Sfil site, see, Holmes et al Science. 253 1278-1280 (1991 )) in the unique Xhol and Notl sites
- a secondary cDNA library was generated in order to preferentially represent the 5' ends of the primary cDNA clones
- Sp6 RNA was generated from the primary library (described above), and this RNA was used to generate a random primed cDNA library in the vector pSST-AMY 0 using reagents and protocols from Life Technologies (Super Script Plasmid System, referenced above)
- the double stranded cDNA was sized to 500-1000 bp, hnkered with blunt to Notl adaptors cleaved with Sfil, and cloned into Sfil/Notl cleaved vector pSST-AMY 0 is a cloning vector that has a yeast alcohol dehydrogenase promoter preceding the cDNA cloning sites and the mouse amylase sequence (the mature sequence without the secretion signal) followed by the yeast alcohol dehydiogenase terminator, after the cloning sites
- DNA from the library described in paragraph 2 above was chilled on ice to which was added electrocompetent DH 10B bacteria (Life Technologies, 20 ml) The bacte ⁇ a and vector mixtuie was then electroporated as recommended by the manufacturer Subsequently, SOC media (Life Technologies, I ml) was added and the mixture was incubated at 37 ° C for 30 minutes The ti anstormants were then plated onto 20 standai d 150 mm LB plates containing ampicillin and incubated for 16 hours (37° C) Positive colonies were scraped off the plates and the DNA was isolated from the bacterial pellet using standard protocols, e g , CsCl-gradient The purified DNA was then carried on to the yeast protocols below
- the yeast methods were divided into three categories ( 1 ) Transformation of yeast with the plasmid/cDNA combined vector, (2) Detection and isolation of yeast clones secreting amylase, and (3) PCR amplification of the insert directly from the yeast colony and purification of the DNA for sequencing and further analysis
- yeast strain used was HD56-5A (ATCC-90785) This strain has the following genotype MAT alpha, ura3-52, leu2-3, leu2- 1 12, h ⁇ s3-l 1 , h ⁇ s3- 15, MAL + , SUC + , GAL +
- yeast mutants can be employed which have deficient post translational pathways Such mutants may have translocation deficient alleles in seel 1 , secll, sec ⁇ l, with truncated secl ⁇ being most preferred
- antagonists including antisense nucleic acids and/or ligands
- which interfere with the normal operation of these genes, other proteins implicated in this post translation pathway e g , SEC61p, SEC72p, SEC62p, SEC63p, TDJlp or SSAl p-4p
- the complex formation of these proteins may also be preferably employed in combination with the amylase-expressing yeast
- the selective media used was a synthetic complete dextrose agar lacking uracil (SCD-Uia) prepared as described in Kaiser et al , Methods in Yeast Genetics Cold Spring Harbor Press, Cold Sp ⁇ ng Harbor, NY, p 208-210 (1994) Transformants were grown at 30 °C for 2-3 da>s
- the detection of colonies secreting amylase was performed by including red starch in the selective growth media Starch was coupled to the red dye (Reactive Red-120, Sigma) as per the procedure described by Biely et al , Anal Biochem .
- the coupled starch was incorporated into the SCD Ura agar plates at a final concentration of 0 1 % (w/v), and was buffered with potassium phosphate to a pH of 7 0 (50-100 mM final concentration)
- the underlined regions ot the oligonucleotides annealed to the ADH promoter legion and the amylase region, respectively, and amplified a 307 bp region from vector pSST-AMY 0 when no insert was present
- the first 18 nucleotides of the 5 end of these oligonucleotides contained annealing sites lor the sequencing primers, wherein these sequences may differ depending upon the sequencing primers employed
- the total product ot the PCR reaction from an empty vector was 343 bp
- signal sequence-tused cDNA resulted in considerably longer nucleotide sequences
- an aliquot of the reaction (5 ⁇ l) was examined by agarose gel electrophoresis in a 1 % agarose gel using a T ⁇ s-Borate EDTA (TBE) buffering system as described by Sambrook et al , supra Clones resulting in a single strong PCR product largei than 400 bp weie
- DNA43509 A cDNA sequence isolated in the above screen was found, by BLAST and FastA sequence alignment, to have sequence homology to a nucleotide sequence encoding human A4 protein This isolated cDNA sequence is herein designated DNA43509 Based on the sequence homology, probes were generated from the sequence of the DNA43509 molecule and used to screen a human fetal lung library (LIB25) prepared as described in paragraph 1 above
- the cloning vector was pRK5B (pRK5B is a precursor of pRK5D that does not contain the Sfil site, see, Holmes et al , Science, 253 1278 1280 (1991 )), and the cDNA size cut was less than 2800 bp
- a pair of PCR primers (forward and reverse) were synthesized based on the DNA43509 sequence forward PCR primer 5'-CGTTTTGCAGAACCTACTCAGGCAG 3 (SEQ ID NO 73) reverse PCR primer
- an oligonucleotide hybridization probe was synthesized to confirm the amplification hybridization probe 5'-AAAGTGCTGCTGCTGGGTCTGCAGACGCGATGGATAACGT-3' (SEQ ID NO 75) Using the above described primers and library, a full length clone was identified (DNA49645 1347, Figure
- SEQ ID NO 26 that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 131-133 and ending at the stop codon found at nucleotide positions 587 589 (see Figure 26)
- the predicted polypeptide precursor is 152 amino acids long has a calculated molecular weight of approximately 17,170 daltons and an estimated pi of approximately 9 62
- Analysis of the full-length PR0772 sequence shown in Figure 27 evidences the presence of the following a potential type II transmembrane domain from about amino acid 26 to about ammo acid 42, other potential transmembrane domains from about amino acid 44 to about amino acid 65, fiom about amino acid 81 to about amino acid 101 and from about amino acid 109 to about amino acid 129, leucine zipper pattern sequences from about amino acid 78 to about amino acid 100 and from about amino acid 85 to about amino acid 107 an N-my ⁇ stoylation site from about amino acid 1 10 to about amino acid 1 16, and a ribonucleo
- EXAMPLE 1 Isolation of cDNA Clones Encoding Human PRO703
- the extracellular domain (ECD) sequences (including the secretion signal, it any) of from about 950 known secreted proteins from the Swiss Prot public protein database were used to search expressed sequence tag (EST) databases
- the EST databases included public EST databases (e g , GenBank) and a proprietary EST DNA database (LIFESEQ ® , Incyte Pharmaceuticals, Palo Alto, CA)
- the search was performed using the computer program BLAST or BLAST2 ( Altshul et al , Methods in Enzymology, 266 460-480 ( 1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap” (Phil Green, University of Washington, Seattle, Washington) A consensus DNA
- oligonucleotides were synthesized 1 ) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for the PRO703 sequence
- Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length
- the probe sequences are typically 40-55 bp in length
- additional oligonucleotides are synthesized when the consensus sequence is greater than about 1 -1 5 kbp
- DNA from the libraries was screened by PCR amplification, as per Ausubel et al , Current Protocols in Molecular Biology, with the PCR primer pair A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs
- Forward and reverse PCR primers were synthesized forward PCR primer 5'-GAGAGCCATGGGGCTCCACCTG-3' (SEQ ID NO 76) reverse PCR primer
- a synthetic oligonucleotide hybridization probe was constructed having the sequence hybridization probe 5'-CCAGTGCCAGGATACCTCTCTTCCCCCCAGAGCATAACAGACACG-3' (SEQ ID NO 80)
- SEQ ID NO 80 sequence hybridization probe 5'-CCAGTGCCAGGATACCTCTCTTCCCCCCAGAGCATAACAGACACG-3'
- RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227)
- the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commerciall) available reagents such as those from Invitrogen, San Diego CA
- the cDNA was primed with ohgo dT containing a Notl site, linked with blunt to Sail hemikinased adaptors, cleaved with Notl, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD, pRK5B is a precursor of pRK5D that does not contain the Sf ii site, see Holmes et al , Science. 253 1278- 1280 ( 1991 )) in the unique Xhol and Notl sites
- DNA50913-1287 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 1 15-1 17 and ending at the stop codon at nucleotide positions 2305-2307 ( Figure 28, SEQ ID NO 28)
- the predicted polypeptide precursor is 730 amino acids long ( Figure 29)
- the full-length PRO703 protein shown in Figure 29 has an estimated molecular weight of about 78,644 daltons and a pi ofabout 7 65
- Important regions of the amino acid sequence encoded by nucleotides 1 15-2304 of PRO703 include a cAMP- and cGMP-dependent protein kinase phosphorylation site from about amino acid 136 to about amino acid 140, a type II transmembrane domain from about amino acid 45 to about amino acid 65, an other transmembrane domain from about amino acid 379 to about amino acid 398, N-glycosylation sites from about amino acid 37 to about ammo acid 41 and from about amino acid 483
- EXAMPLE 12 Isolation of cDNA Clones Encoding Human PRQ792
- the extracellular domain (ECD) sequences (including the secretion signal, if any) of from about 950 known secreted proteins from the Swiss-Prot public protein database were used to search expressed sequence tag (EST) databases
- the EST databases included public EST databases (e g , GenBank) and a proprietary EST DNA database (LIFESEQ ® , Incyte Pharmaceuticals, Palo Alto, CA)
- the search was performed using the computei program BLAST or BLAST2 ( Altshul et al , Methods in Enzymology, 266 460-480 ( 1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle Washington)
- DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above A positive library was then used to isolate clones encoding the PR0792 gene using the probe oligonucleotide and one of the PCR primers
- RNA for construction of the cDNA libraries was isolated from human bone marrow tissue (LIB255)
- the cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, CA
- the cDNA was primed with ohgo dT containing a Notl site, linked with blunt to Sail hemikinased adaptors, cleaved with Notl, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD , pRK5B is a precursor of pRK5D that does not contain the Sfil site, see, Holmes et al , Science, 253 1278-1280 (1991 )) in the unique Xhol and Notl sites
- DNA sequencing of the clones isolated as described above gave the full-length DNA sequence encoding the native sequence PR0792 [herein designated as DNA56352 1358] (SEQ ID NO 30) and the derived protein sequence for PR0792
- the extracellular domain (ECD) sequences (including the secretion signal if any) of from about 950 known secreted proteins from the Swiss Prot public protein database were used to search expressed sequence tag (EST) databases
- the EST databases included public EST databases (e g , GenBank, Merck/Wash U) and a proprietary EST DNA database (LIFESEQ ® , Incyte Pharmaceuticals, Palo Alto, CA)
- the search was performed using the computer program BLAST or BLAST2 (Altshul et al , Methods in Enzymology, 266 460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap” (Phil Green, University of Washington, Seattle, Washington)
- DNA49818 An initial consensus DNA sequence was assembled relative to other EST sequences using phrap The initial consensus DNA sequence was then extended using repeated cycles of BLAST and phrap to extend the initial consensus sequence as far as possible using the sources of EST sequences discussed above The extended consensus sequence obtained is herein designated DNA49818
- an N glycosylation site is at about amino acids 138-141 of SEQ ID NO 33
- short-chain alcohol dehydrogenase family protein homologies are at about amino acids 10-22, 81 -91 , 134 171 and 176-185 of SEQ ID NO 33
- the corresponding nucleotides can be routinel) determined given the sequences provided herein
- PR021 -, PRO 1330-, PRO 1449 PR0237-, PR0324-, PR0351 -, PR0362 , PR0615-, PR0531 -, PR0538 , PR03664-, PR0618-, PR0772 , PRO703 PR0792- and PR0474-encod ⁇ ng genes are amplified in the genome of certain human lung, colon and/or breast cancers and/or cell lines Amplification is associated with overexpression of the gene product, indicating that the pol)pept ⁇ des are useful targets toi therapeutic intervention in certain cancers such as colon, lung, breast and other cancers
- Therapeutic agents ma) take the form of antagonists of PR0213, PRO1330, PR01449, PR0237 PR0324 PR0351 , PR0362, PR0615 PR0531 , PR0538, PR03664 PR0618, PR0772, PRO703, PR0792 oi PR0474 polypeptide, for example, mu ⁇ ne-human chimeric, humanized or human
- the starting material for the screen was genomic DNA isolated from a variety cancers
- the DNA is quantitated precisely, e g , fluoromet ⁇ cally
- DNA was isolated from the cells often normal healthy individuals which was pooled and used as assay controls for the gene copy in healthy individuals (not shown)
- the 5' nuclease assay for example, TaqManTM
- real-time quantitative PCR for example, ABI P ⁇ zm 7700 Sequence Detection SystemTM (Perkin Elmer, Applied Biosystems Division, Foster City, CA)
- the results were used to determine whether the DNA encoding PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351 , PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 is over-represented in any of the primary lung or colon cancers or cancer cell lines or breast cancer cell lines that were
- the results of the TaqmanTM are reported in delta ( ⁇ ) CT units
- One unit corresponds to 1 PCR cycle or approximately a 2-fold amplification relative to normal, two units corresponds to 4-fold, 3 units to 8-fold amplification and so on Quantitation was obtained using primers and a TaqmanTM fluorescent probe derived from the PR0213-, PRO1330-, PR01449-, PR0237-, PR0324-, PR0351-, PR0362-, PR0615-, PR0531-, PR0538-, PR03664-, PR0618-, PR0772-, PRO703-, PR0792- or PR0474-encodmg gene Regions of PR0213 , PRO 1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531, PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 which are most likely to contain unique nucleic acid sequences and which are least likely
- PR0213, PRO1330 and PR01449 (DNA30943-1163, DNA64907- 1 163 and DNA64908-1 163, respectively)
- PR0362 (DNA45416-1251 ) 45416 tm f l 5'-TGTGGCACAGACCCAATCCT-3' (SEQ ID NO 102)
- PR0531 (DNA48314-1320): 48314.tm.fl : 5'-TTCAAGTTCCTGAAGCCGATTAT-3' (SEQ ID NO: 108)
- PR0538 & PR03664 (DNA48613-1268 & DNA48614-1268):
- PR0618 (DNA49152-1324): 49152.tm.fl :
- PRO703 (DNA50913-1287) 50913 tm fl
- PR0474 (DNA56045-1380) 56045 tm f 1 5' AAACTCCAACCTGTATCAGATGCA 3' (SEQ ID NO 129)
- the 5 nuclease assay reaction is a fluorescent PCR-based technique which makes use of the 5' exonuclease acti vit) of Taq DNA polymerase enzyme to monitor amplification in real time 1 wo oligonucleotide primers are used to generate an amplicon typical ot a PCR reaction
- a third oligonucleotide or probe is designed to detect nucleotide sequence located between the two PCR p ⁇ meis
- the probe is non-extendible by Taq DNA polymerase enzyme, and is labeled with a reporter fluorescent dye and a quencher fluorescent d>e Any laser-induced emission from the reporter dye is quenched by the quenching dye when the two dyes are located close together as they are on the probe.
- the Taq DNA polymerase enzyme cleaves the probe in a template-dependent manner.
- the resultant probe fragments disassociate in solution, and signal from the released reporter dye is free from the quenching effect of the second fluorophore.
- One molecule of reporter dye is liberated for each new molecule synthesized, and detection of the unquenched reporter dye provides the basis for quantitative interpretation of the data.
- the 5' nuclease procedure is run on a real-time quantitative PCR device such as the ABI Prism 7700TM
- the system consists of a thermocycler, laser, charge-coupled device (CCD) camera and computer.
- the system amplifies samples in a 96- well format on a thermocycler.
- laser-induced fluorescent signal is collected in real-time through fiber optics cables for all 96 wells, and detected at the CCD.
- the system includes software for running the instrument and for analyzing the data.
- Ct 5' Nuclease assay data are initially expressed as Ct, or the threshold cycle. This is defined as the cycle at which the reporter signal accumulates above the background level of fluorescence.
- the Ct values are used as quantitative measurement of the relative number of starting copies of a particular target sequence in a nucleic acid sample when comparing cancer DNA results to normal human DNA results.
- Table 4 describes the stage, T stage and N stage of various primary tumors which were used to screen the PR0213, PRO1330, PR01449, PR0237, PR0324, PR0351, PR0362, PR0615, PR0531 , PR0538, PR03664, PR0618, PR0772, PRO703, PR0792 or PR0474 compounds of the invention.
- DNA Preparation DNA was prepared from cultured cell lines, primary tumors, and normal human blood The isolation was performed using purification kit buffer set and protease and all from Qiagen according to the manufacturer s instructions and the description below Cell cultuie sis
- Tumor samples were weighed and placed into 50 ml conical tubes and held on ice Processing was limited to no more than 250 mg tissue per preparation (1 tip/preparation)
- the protease solution was freshly prepared by diluting into 6 25 ml cold ddH 2 0 to a final concentration of 20 mg/ml and stored at 4°C G2 buffer (20 ml) was prepared by diluting DNAse A to a final concentration of 200 mg/ml (from 100 mg/ml stock)
- the tumor tissue was homogenated in 19 ml G2 buffer for 60 seconds using the large tip of the polytron in a laminar-flow TC hood in order to avoid inhalation of aerosols, and held at room temperature Between samples, the polytron was cleaned by spinning at 2 x 30 seconds each in 2L ddH 2 0, followed by G2 buffer (50 ml) If tissue was still present on the generator tip, the apparatus was disassembled and cleaned
- nuclei were suspended into 2 ml Cl buffer (4"C) and 6 ml ddHoO (4"C) Vortexing was repeated until the pellet was white The nuclei were then suspended into the residual buffer using a 200 ⁇ l tip G2 buffer ( 10 ml) was added to the suspended nuclei while gently vortexing, followed by vigorous vortexing for 30 seconds Qiagen protease was added (200 ul) and incubated at 50°C for 60 minutes The incubation and centrifugation were repeated until the lysates were cleai (e g , incubating additional
- Genomic DNA was equilibrated ( 1 sample per maxi tip preparation) with 10 ml QBT buffer QF elution buffer was equilibrated at 50"C The samples were vortexed for 30 seconds, then loaded onto equilibrated tips and drained by gravity The tips were washed with 2 x 15 ml QC buffer The DNA was eluted into 30 ml silanized, autoclaved 30 ml Corex tubes with 15 ml QF buffer (50"C) Isopropanol ( 10 5 ml) was added to each sample, the tubes covered with parafin and mixed by repeated inversion until the DNA precipitated Samples were pelleted by centrifugation in the SS-34 rotor at 15,000 rpm for 10 minutes at 4"C The pellet location was marked, the supernatant discarded, and 10 ml 70% ethanol (4°C) was added Samples were pelleted again by centrifugation on the SS 34 rotor at 10,000 rpm for 10 minutes at
- DNA levels in each tube were quantified by standard A 26( / A 2M , spectrophotometry on a 1 20 dilution (5 ⁇ l DNA + 95 ⁇ l ddH,0) using the 0 1 ml quartz cuvettes in the Beckman DU640 spectrophotometer A, 6 ,/A, M) ratios were in the range of 1 8-1 9
- Each DNA sample was then diluted further to approximately 200 ng/ml in TE (pH 8 5) If the original material was highly concentrated (about 700 ng/ ⁇ l), the material was placed at 50°C for several hours until resuspended
- Fluoromet ⁇ c DNA quantitation was then performed on the diluted material (20-600 ng/ml) using the manufacturer's guidelines as modified below This was accomplished by allowing a Hoeffer DyNA Quant 200 fluorometer to warm-up for about 15 minutes
- the Hoechst dye working solution (#H33258, 10 ⁇ l, prepared withm 12 hours of use) was diluted into 100 ml 1 x TNE buffer A 2 ml cuvette was filled with the fluorometer solution, placed into the machine, and the machine was zeroed pGEM 3Zf (+) (2 ⁇ l, lot #360851026) was added to 2 ml ot fluorometer solution and calibrated at 200 units An additional 2 ⁇ l of pGEM 3Zf (4-) DNA was then tested and the reading confirmed at 400 +/- 10 units Each sample was then read at least in triplicate When 3 samples were found to be within 10% of each other, their average was taken and this value was used as the quantification value
- PR03664, PR0618, PR0772, PRO703, PR0792 oi PR0474 compounds ot the invention were screened in the following primary tumors and the resulting ⁇ Ct values are reported in Table 5 Table 5 ⁇ Ct values in lung and colon primary tumor and cell line models
- PRQ213, PRO1330 and PRQ1449 (DNA30943-1 163, DNA64909-1 163 and DNA64908-1 163. respectively)
- PR0237 would be expected to have utility in cancer therapy
- PRQ351 (DNA40571 1315)
- Table 5 The ⁇ Ct values for DN A40571 - 1315 in a variety of tumors are reported in Table 5 A ⁇ Ct of > 1 was typically used as the threshold value tor amplification scoring as this represents a doubling of gene cop) Table 5 indicates that significant amplification of nucleic acid encoding PR0351 occu ⁇ ed in primary lung tumors LT9 LT10, LTl 1 , LT13, LT15, LT16, LT17, LT18, LT19 and LT21 Because amplification of DN A40571 1 1 occurs in lung tumoi s, it is highly probable to play a significant role in tumor formation or growth As a result, antagonists (e g , antibodies) directed against the PR0351 would be expected to have utility in cancer therapy
- PRQ362 (DNA45416- 1251 )
- Table 5 The ⁇ Ct values for DNA48304-1323 in a variety of tumors are reported in Table 5 A ⁇ Ct ot >1 was typically used as the threshold value for amplification scoring, as this represents a doubling of gene copy Table 5 indicates that significant amplification of nucleic acid encoding PR0615 occurred ( 1 ) in primary lung tumors LT3, LT6, LT7, LT9, LTIO, LTl 1 , LT12, LT13, LT15, LT16, LT17, LT19 and LT21 , and (2) in primary colon tumors CT2, CT3, CT10, CT12, CT14, CT15, CT16, CT17, CT4, CT5, CT1 1 and CT18
- PRO703 (DNA50913-1287)
- Table 5 indicates that significant amplification of nucleic acid encoding PRO703 occurred (1 ) in primary lung tumors LTla, LT3, LT6, LT7, LTIO, LTl 1 , LTl 2, LT13, LT15, LT16 LT17, LT19 and LT21 , and (2) in primary colon tumors CT2, CT3, CT8, CT10, CT12, CT14, CT15, CT16, CT17, CT1 CT4, CT5, CT6, CT7, CT1 1 and CT18 Because amplification of DNA50913-1287 occurs in various tumors, it is highly probable to play a significant role in tumor formation or growth As a result, antagonists (e g , antibodies) directed against the PRO703 would
- Table 5 The ⁇ Ct values for DNA56045-1380 in a variety of tumors are reported in Table 5 A ⁇ Ct of >1 was typically used as the threshold value for amplification scoring, as this represents a doubling of gene copy Table 5 indicates that significant amplification of nucleic acid encoding PR0474 occurred (1 ) in primary lung tumors LTla, LT3, LT6, LT7, LT9, LTIO, LT1 1 , LT12, LT13, LT15, LT16, LT17, LT18, LT19 and LT21 , and (2) in primary colon tumors CT2, CT3, CT4, CT5, CT6, CT8, CT10, CT1 1 , CT12, CT14, CT15, CT16, CT17, CT1 and CT18
- In situ Hybridization is a powerful and versatile technique for the detection and localization of nucleic acid sequences within cell or tissue preparations It may be useful, for example, to identify sites of gene expression, analyze the tissue distribution of transcription, identify and localize viral infection, follow changes in specific mRNA synthesis, and aid in chromosome mapping
- RNAs 1 0 ⁇ l DNA template (1 ⁇ g) 1 0 ⁇ l H,0
- the tubes were incubated at 37 °C for one hour A total of 1 0 ⁇ l RQ1 DNase was added, followed by incubation at 37 °C tor 15 minutes A total of 90 ⁇ l TE ( 10 M Tris pH 7 6/1 mM EDTA pH 8 0) was added and the mixture was pipetted onto DE81 paper The remaining solution was loaded in a MICROCON-50 ultrafiltration unit, and spun using program 10 (6 minutes) The filtration unit was inverted over a second tube and spun using program 2 (3 minutes) After the final recovery spin, a total of 100 ⁇ l TE was added, then 1 ⁇ l of the final product was pipetted on DE81 paper and counted in 6 ml of BIOFLUOR IITM The probe was run on a TBE/urea gel A total of 1 -3 ⁇ l of the probe or 5 ⁇ l of RNA Mrk III was added to 3 ⁇ l of
- the slides were removed from the freezer, placed on aluminum trays, and thawed at room temperature for 5 minutes The trays were placed in a 55 °C incubator for five minutes to reduce condensation The slides were fixed for 10 minutes in 4% paraformaldehyde on ice in the fume hood, and washed in 0 5 x SSC for 5 minutes, at room temperature (25 ml 20 x SSC + 975 ml SQ H 2 0) After deproteination in 0 5 ⁇ g/ml proteinase K for 10 minutes at 37°C (12 5 ⁇ l of 10 mg/ml stock in 250 ml prewarmed RNAse-free RNAse buffer), the sections were washed in 0 5 x SSC for 10 minutes at room temperature The sections were dehydrated in 70%, 95%, and 100% ethanol, 2 minutes each
- the slides were laid out in a plastic box lined with Box buffer (4 x SSC, 50% formamide) - saturated filter paper
- the tissue was covered with 50 ⁇ l of hybridization buffer (3 75 g dextran sultate + 6 ml SQ H 2 0), vortexed, and heated in the microwave for 2 minutes with the cap loosened After cooling on ice, 18 75 ml formamide, 3 75 ml 20 x SSC, and 9 ml SQ H 2 0 were added, and the tissue was vortexed well and incubated at 42 °C for 1 -4 hours D Hybiidization
- PRO703. PRQ792 or PRQ474 as a hybridization probe The following method describes use of a nucleotide sequence encoding a PR0213, PRO 1330, PRO 1449,
Abstract
Description
Claims
Priority Applications (246)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU22248/00A AU2224800A (en) | 1999-03-08 | 2000-01-06 | Compositions and methods for the treatment of tumor |
JP2000603377A JP2004513602A (en) | 1999-03-08 | 2000-02-18 | Secreted and transmembrane polypeptides and nucleic acids encoding them |
CA002361840A CA2361840A1 (en) | 1999-03-08 | 2000-02-18 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
KR1020017011399A KR20030002292A (en) | 1999-03-08 | 2000-02-18 | Secreted and Transmembrane Polypeptides and Nucleic Acids Encoding the Same |
PCT/US2000/004341 WO2000053756A2 (en) | 1999-03-08 | 2000-02-18 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP00907314A EP1263948A2 (en) | 1999-03-08 | 2000-02-18 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
JP2000603379A JP2004516227A (en) | 1999-03-08 | 2000-03-02 | Compositions and methods for treating immune-related diseases |
AU35144/00A AU3514400A (en) | 1999-03-08 | 2000-03-02 | Compositions and methods for the treatment of immune related diseases |
KR1020017011406A KR20010103046A (en) | 1999-03-08 | 2000-03-02 | Compositions and Methods for the Treatment of Immune Related Diseases |
EP00913764A EP1220905A2 (en) | 1999-03-08 | 2000-03-02 | Composition and methods for the treatment of immune related diseases |
CA002362427A CA2362427A1 (en) | 1999-03-08 | 2000-03-02 | Compositions and methods for the treatment of immune related diseases |
PCT/US2000/005841 WO2000053758A2 (en) | 1999-03-08 | 2000-03-02 | Compositions and methods for the treatment of immune related diseases |
CA002491610A CA2491610A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP06000582A EP1666495A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP06000588A EP1690873A3 (en) | 1999-12-01 | 2000-12-01 | Composition and methods for the diagnosis of tumours |
PCT/US2000/032678 WO2001040466A2 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP06000587A EP1690872A3 (en) | 1999-12-01 | 2000-12-01 | Composition and methods for the diagnosis of tumours |
EP10005292A EP2228446A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptieds and nucleic acids encoding the same |
EP00983846A EP1250426A2 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding same |
AU20554/01A AU2055401A (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP06000586A EP1688497A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP06000585A EP1661996A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
CA2709291A CA2709291A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP06000583A EP1686134A3 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
CA002496312A CA2496312A1 (en) | 1999-12-01 | 2000-12-01 | Colon tumour marker pro4799 polypeptides and nucleic acids encoding the same |
JP2001542531A JP2004522404A (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding them |
CA002490909A CA2490909A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
CA002492070A CA2492070A1 (en) | 1999-12-01 | 2000-12-01 | Lung tumor marker pro4329 polypeptides and nucleic acids encoding the same |
CA002492049A CA2492049A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
CA002491258A CA2491258A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP05025102A EP1672070A3 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
CA002391455A CA2391455A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
CA002491433A CA2491433A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
CA002494705A CA2494705A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP06000589A EP1661997A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP06000581A EP1666494A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
CA002490853A CA2490853A1 (en) | 1999-12-01 | 2000-12-01 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP06000584A EP1669371A3 (en) | 1999-12-01 | 2000-12-01 | Composition and methods for the diagnosis of tumours |
US09/828,366 US20020010137A1 (en) | 1997-09-18 | 2001-04-05 | Methods and compositions for inhibiting neoplastic cell growth |
US09/918,585 US20030060406A1 (en) | 1997-10-17 | 2001-07-30 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,295 US20020156006A1 (en) | 1997-10-17 | 2001-10-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,193 US20030073624A1 (en) | 1997-10-17 | 2001-10-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,299 US20030199435A1 (en) | 1997-10-17 | 2001-10-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,192 US20020177553A1 (en) | 1997-10-17 | 2001-10-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,189 US6972325B2 (en) | 1997-10-17 | 2001-10-15 | PRO273 polypeptides |
US09/978,194 US20030195333A1 (en) | 1997-10-17 | 2001-10-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,188 US20030139328A1 (en) | 1997-10-17 | 2001-10-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,191 US20030050239A1 (en) | 1997-10-17 | 2001-10-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,298 US20030134785A1 (en) | 1997-10-17 | 2001-10-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/981,915 US7285623B2 (en) | 1997-10-17 | 2001-10-16 | PRO337 polypeptides |
US09/978,608 US20030045462A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,544 US20030199436A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,665 US7294700B2 (en) | 1997-10-17 | 2001-10-16 | Anti-PRO846 antibodies |
US09/978,585 US20030049633A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,681 US20030195148A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,403 US20030050240A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/981,915 US20030054986A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,824 US20050124789A9 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,564 US7195760B2 (en) | 1997-10-17 | 2001-10-16 | Anti-pro363 antibodies |
US09/978,643 US20030104998A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,757 US20030083248A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,423 US20030069178A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,375 US7196165B2 (en) | 1997-10-17 | 2001-10-16 | PRO363 polypeptides |
US09/978,802 US20030199674A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,697 US20020169284A1 (en) | 1997-10-17 | 2001-10-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,824 US20030055216A1 (en) | 1997-10-17 | 2001-10-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/210,028 US20030203446A1 (en) | 1998-10-07 | 2001-10-18 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/152,388 US20040223964A1 (en) | 1998-03-17 | 2001-10-18 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/145,089 US7208575B2 (en) | 1998-10-07 | 2001-10-19 | PRO531 polypeptides |
US10/160,502 US7220835B2 (en) | 1998-07-30 | 2001-10-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/164,728 US20030186368A1 (en) | 1998-05-13 | 2001-10-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/145,124 US20030190701A1 (en) | 1998-04-30 | 2001-10-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/165,067 US7279553B2 (en) | 1998-05-13 | 2001-10-19 | PRO1083 polypeptides |
US10/164,749 US20040029218A1 (en) | 1998-10-07 | 2001-10-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/165,036 US20050227342A1 (en) | 1998-10-07 | 2001-10-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/166,709 US20030104536A1 (en) | 1998-10-07 | 2001-10-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/164,929 US20030194781A1 (en) | 1998-03-30 | 2001-10-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/145,017 US20030186365A1 (en) | 1998-03-26 | 2001-10-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/165,247 US7112657B2 (en) | 1998-10-07 | 2001-10-19 | PRO697 polypeptides |
US10/143,029 US7105640B2 (en) | 1997-10-17 | 2001-10-19 | Anti-pro792 antibodies |
US10/162,521 US7067628B2 (en) | 1998-03-17 | 2001-10-19 | PRO788 polypeptides |
US10/164,829 US20030194780A1 (en) | 1998-04-29 | 2001-10-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/013,922 US20030195345A1 (en) | 1997-10-17 | 2001-10-21 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/017,084 US20030203402A1 (en) | 1997-10-17 | 2001-10-24 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/002,967 US20030148373A1 (en) | 1997-10-17 | 2001-10-24 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/020,445 US20030198994A1 (en) | 1997-10-17 | 2001-10-24 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/017,083 US20030148376A1 (en) | 1997-10-17 | 2001-10-24 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/999,829 US20030195344A1 (en) | 1997-10-17 | 2001-10-24 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/017,086 US7122375B2 (en) | 1997-10-17 | 2001-10-24 | PRO274 nucleic acids |
US09/999,833 US6916648B2 (en) | 1997-10-17 | 2001-10-24 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/017,081 US20030049684A1 (en) | 1997-10-17 | 2001-10-24 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/017,085 US6974696B2 (en) | 1997-10-17 | 2001-10-24 | PRO853 nucleic acids |
US09/999,832 US20020192706A1 (en) | 1997-10-17 | 2001-10-24 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/999,830 US20030077700A1 (en) | 1997-10-17 | 2001-10-24 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/999,832 US7132283B2 (en) | 1997-10-17 | 2001-10-24 | PRO273 polypeptides |
US09/999,834 US20030064407A1 (en) | 1997-10-17 | 2001-10-24 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/013,921 US20030068648A1 (en) | 1997-10-17 | 2001-10-25 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/013,918 US20030211091A1 (en) | 1997-10-17 | 2001-10-25 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/013,929 US7019124B2 (en) | 1997-10-17 | 2001-10-25 | PRO788 nucleic acids |
US10/013,920 US20040006219A1 (en) | 1997-10-17 | 2001-10-25 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/013,927 US7189529B2 (en) | 1997-10-17 | 2001-10-25 | PRO792 nucleic acids |
US10/016,177 US20030073131A1 (en) | 1997-10-17 | 2001-10-25 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/013,923 US7169912B2 (en) | 1997-10-17 | 2001-10-25 | PRO1017 nucleic acids |
US10/013,928 US20030215905A1 (en) | 1998-10-07 | 2001-10-25 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/013,925 US7037710B2 (en) | 1997-10-17 | 2001-10-25 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/013,926 US7074593B2 (en) | 1998-04-01 | 2001-10-25 | PRO 703 nucleic acids |
US10/013,917 US7029874B2 (en) | 1998-03-17 | 2001-10-25 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/990,456 US20020137890A1 (en) | 1997-03-31 | 2001-11-14 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/028,072 US20030004311A1 (en) | 1997-06-18 | 2001-12-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US09/978,187 US20030096744A1 (en) | 1997-10-17 | 2002-01-28 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/119,480 US20040087769A1 (en) | 1998-09-10 | 2002-04-09 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,047 US20030077778A1 (en) | 1997-03-31 | 2002-04-11 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,045 US20030073210A1 (en) | 1997-03-31 | 2002-04-11 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,059 US20030190721A1 (en) | 1997-03-31 | 2002-04-11 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,042 US20030096386A1 (en) | 1997-03-31 | 2002-04-11 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,046 US20030194791A1 (en) | 1997-03-31 | 2002-04-11 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,040 US20030082759A1 (en) | 1997-03-31 | 2002-04-11 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,051 US20030092147A1 (en) | 1997-03-31 | 2002-04-11 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,044 US20030190717A1 (en) | 1997-03-31 | 2002-04-11 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,041 US20030077776A1 (en) | 1997-03-31 | 2002-04-11 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,061 US20030082761A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,062 US20030077779A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,052 US20030199052A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,043 US7220831B2 (en) | 1997-03-31 | 2002-04-12 | PRO235 polypeptides |
US10/121,049 US20030022239A1 (en) | 1997-06-18 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,054 US20030199054A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,063 US20030199055A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,050 US20030054516A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,055 US20030190718A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,060 US20030190722A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,057 US20030190719A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,053 US20030199053A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,048 US20030199051A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,058 US20030190720A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/121,056 US20030082760A1 (en) | 1997-03-31 | 2002-04-12 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,108 US7635478B2 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,262 US20030049816A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,292 US20030073211A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,215 US7291329B2 (en) | 1997-03-31 | 2002-04-15 | Antibodies against PRO4406 |
US10/123,156 US20030194792A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,213 US20030199057A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,236 US20030068795A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,214 US7343721B2 (en) | 1997-03-31 | 2002-04-15 | PRO4406 polypeptide |
US10/123,212 US7276577B2 (en) | 1997-03-31 | 2002-04-15 | PRO1866 polypeptides |
US10/123,322 US20030199059A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,261 US20030068796A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,157 US20030190725A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,109 US20030190723A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,213 US7193048B2 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,291 US20030199058A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,235 US20030082762A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,771 US20030199060A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,155 US20030068794A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,154 US20030190724A1 (en) | 1997-03-31 | 2002-04-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,902 US20030077781A1 (en) | 1997-03-31 | 2002-04-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,905 US7285625B2 (en) | 1997-06-18 | 2002-04-16 | PRO536 polypeptides |
US10/123,910 US7329404B2 (en) | 1997-03-31 | 2002-04-16 | Antibodies against PRO1310 |
US10/123,904 US20030022328A1 (en) | 1997-03-31 | 2002-04-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,912 US20030100087A1 (en) | 1997-03-31 | 2002-04-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,909 US7193049B2 (en) | 1997-03-31 | 2002-04-16 | PRO862 polypeptides |
US10/123,906 US20030190726A1 (en) | 1997-03-31 | 2002-04-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,903 US20030073212A1 (en) | 1997-03-31 | 2002-04-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,907 US7084258B2 (en) | 1997-03-31 | 2002-04-16 | Antibodies against the PRO862 polypeptides |
US10/123,911 US7408032B2 (en) | 1997-03-31 | 2002-04-16 | PRO1188 polypeptides |
US10/123,913 US20030203462A1 (en) | 1997-03-31 | 2002-04-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,905 US20030087344A1 (en) | 1997-06-18 | 2002-04-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/123,908 US7335728B2 (en) | 1997-03-31 | 2002-04-16 | PRO1310 polypeptides |
US10/124,817 US20030077786A1 (en) | 1997-03-31 | 2002-04-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/124,813 US7312307B2 (en) | 1997-03-31 | 2002-04-17 | PRO1056 polypeptides |
US10/124,814 US7105335B2 (en) | 1997-03-31 | 2002-04-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/124,824 US20030077659A1 (en) | 1997-03-31 | 2002-04-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/125,795 US7304131B2 (en) | 1997-03-31 | 2002-04-17 | PRO1483 polypeptides |
US10/124,816 US20030190728A1 (en) | 1997-03-31 | 2002-04-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/124,820 US20030190729A1 (en) | 1997-03-31 | 2002-04-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/124,822 US7109305B2 (en) | 1997-03-31 | 2002-04-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/124,818 US20030082763A1 (en) | 1997-03-31 | 2002-04-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/124,823 US20030199062A1 (en) | 1997-03-31 | 2002-04-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/124,821 US20030199023A1 (en) | 1997-03-31 | 2002-04-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/125,805 US20030194794A1 (en) | 1997-03-31 | 2002-04-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/124,819 US7285626B2 (en) | 1997-03-31 | 2002-04-17 | PRO1076 polypeptides |
US10/125,704 US7357926B2 (en) | 1997-03-31 | 2002-04-17 | Antibodies against PRO1879 and the use thereof |
US10/125,922 US7309762B2 (en) | 1997-03-31 | 2002-04-19 | PRO1360 polypeptides |
US10/125,927 US20030190731A1 (en) | 1997-03-31 | 2002-04-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/125,932 US7317079B2 (en) | 1997-03-31 | 2002-04-19 | PRO812 polypeptides |
US10/125,924 US7342097B2 (en) | 1997-03-31 | 2002-04-19 | PRO1309 polypeptides |
US10/125,931 US20030199063A1 (en) | 1997-03-31 | 2002-04-19 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/127,831 US20030082689A1 (en) | 1997-03-31 | 2002-04-22 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/128,689 US20030087365A1 (en) | 1997-03-31 | 2002-04-23 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/131,823 US7304132B2 (en) | 1997-03-31 | 2002-04-24 | PRO1693 polypeptides |
US10/131,817 US7291701B2 (en) | 1997-03-31 | 2002-04-24 | PRO1777 polypeptides |
US10/131,825 US7282566B2 (en) | 1997-03-31 | 2002-04-24 | PRO1779 polypeptide |
US10/137,867 US20030207349A1 (en) | 1997-03-31 | 2002-05-03 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/137,865 US20030032155A1 (en) | 1997-03-31 | 2002-05-03 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/137,868 US20030082764A1 (en) | 1997-03-31 | 2002-05-03 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,023 US20030207416A1 (en) | 1997-03-31 | 2002-05-06 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,020 US20030207415A1 (en) | 1997-03-31 | 2002-05-06 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/139,963 US7288625B2 (en) | 1997-03-31 | 2002-05-06 | PRO4395 polypeptides |
US10/139,980 US7247710B2 (en) | 1997-03-31 | 2002-05-06 | PRO4395 antibodies |
US10/140,474 US20030032156A1 (en) | 1997-03-31 | 2002-05-06 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,024 US20040058424A1 (en) | 1997-03-31 | 2002-05-06 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,470 US20030022331A1 (en) | 1997-03-31 | 2002-05-06 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,860 US7307151B2 (en) | 1997-03-31 | 2002-05-07 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,864 US20030207419A1 (en) | 1997-03-31 | 2002-05-07 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,928 US20030068798A1 (en) | 1997-03-31 | 2002-05-07 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,805 US20030207417A1 (en) | 1997-03-31 | 2002-05-07 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,809 US20030207418A1 (en) | 1997-03-31 | 2002-05-07 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,808 US7425621B2 (en) | 1997-03-31 | 2002-05-07 | Antibodies against the PRO4401 polypeptide |
US10/140,865 US20030207420A1 (en) | 1997-03-31 | 2002-05-07 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,925 US20030073215A1 (en) | 1997-03-31 | 2002-05-07 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/140,921 US7317080B2 (en) | 1997-03-31 | 2002-05-07 | PRO4303 polypeptides |
US10/141,754 US7361732B2 (en) | 1997-03-31 | 2002-05-08 | PRO4400 polypeptides |
US10/141,755 US7297764B2 (en) | 1997-03-31 | 2002-05-08 | PRO4318 polypeptides |
US10/141,760 US7342104B2 (en) | 1997-03-31 | 2002-05-08 | Antibodies against the PRO4320 polypeptide |
US10/141,701 US20030207421A1 (en) | 1997-03-31 | 2002-05-08 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/141,756 US7488586B2 (en) | 1997-03-31 | 2002-05-08 | PRO4409 polypeptides |
US10/142,425 US20030207424A1 (en) | 1997-03-31 | 2002-05-09 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/143,113 US7329730B2 (en) | 1997-03-31 | 2002-05-09 | PRO4348 polypeptides |
US10/142,430 US7309766B2 (en) | 1997-03-31 | 2002-05-09 | PRO5774 polypeptides |
US10/143,114 US20030036180A1 (en) | 1997-03-31 | 2002-05-09 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/142,417 US7304133B2 (en) | 1997-03-31 | 2002-05-09 | PRO4389 polypeptides |
US10/142,431 US7285629B2 (en) | 1997-03-31 | 2002-05-10 | Pro5005 polypeptides |
US10/142,423 US20030049817A1 (en) | 1997-03-31 | 2002-05-10 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/143,032 US7408033B2 (en) | 1997-03-31 | 2002-05-10 | PRO5995 polypeptides |
US10/142,419 US7153941B2 (en) | 1997-03-31 | 2002-05-10 | Antibodies that bind PRO4994 polypeptides |
US10/146,730 US20030207427A1 (en) | 1997-03-31 | 2002-05-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/146,792 US20030207428A1 (en) | 1997-03-31 | 2002-05-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/147,528 US20030219885A1 (en) | 1997-03-31 | 2002-05-16 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/147,536 US20040077064A1 (en) | 1997-03-31 | 2002-05-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/147,492 US20030082765A1 (en) | 1997-03-31 | 2002-05-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/147,519 US20030077791A1 (en) | 1997-03-31 | 2002-05-17 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/152,395 US7189534B2 (en) | 1997-03-31 | 2002-05-21 | PRO4320 polynucleotide |
US10/153,934 US20030129695A1 (en) | 1997-03-31 | 2002-05-22 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/156,843 US20030207805A1 (en) | 1997-06-18 | 2002-05-28 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/157,782 US20030077792A1 (en) | 1997-03-31 | 2002-05-29 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/157,786 US20030208055A1 (en) | 1997-03-31 | 2002-05-29 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/158,791 US20030207429A1 (en) | 1997-03-31 | 2002-05-30 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/158,782 US20030082766A1 (en) | 1997-03-31 | 2002-05-30 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/160,498 US20030073216A1 (en) | 1997-03-31 | 2002-05-30 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US10/176,913 US20030022298A1 (en) | 1997-09-15 | 2002-06-20 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
JP2005264293A JP2006068016A (en) | 1999-12-01 | 2005-08-15 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US11/341,175 US7468427B2 (en) | 1997-03-31 | 2006-01-27 | Antibodies to PRO1275 polypeptide |
US11/786,466 US20080182275A1 (en) | 1998-12-22 | 2007-04-10 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
JP2007326613A JP2008161190A (en) | 1999-12-01 | 2007-12-18 | Secreted and transmembrane polypeptide and nucleic acid encoding the same |
JP2007326609A JP2008148701A (en) | 1999-12-01 | 2007-12-18 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
JP2007325484A JP2008148699A (en) | 1999-12-01 | 2007-12-18 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
JP2007326424A JP2008167749A (en) | 1999-12-01 | 2007-12-18 | Secreted and transmembrane polypeptide and nucleic acid encoding the same |
Applications Claiming Priority (22)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1999/005028 WO1999046281A2 (en) | 1998-03-10 | 1999-03-08 | Novel polypeptides and nucleic acids encoding the same |
USPCT/US99/05028 | 1999-03-08 | ||
US12395799P | 1999-03-12 | 1999-03-12 | |
US60/123,957 | 1999-03-12 | ||
US12677399P | 1999-03-29 | 1999-03-29 | |
US60/126,773 | 1999-03-29 | ||
US13023299P | 1999-04-21 | 1999-04-21 | |
US60/130,232 | 1999-04-21 | ||
US13144599P | 1999-04-28 | 1999-04-28 | |
US60/131,445 | 1999-04-28 | ||
PCT/US1999/023089 WO2000021996A2 (en) | 1998-10-13 | 1999-10-05 | Methods and compositions for inhibiting neoplastic cell growth |
USPCT/US99/23089 | 1999-10-05 | ||
USPCT/US99/28313 | 1999-11-30 | ||
PCT/US1999/028313 WO2000032221A2 (en) | 1998-12-01 | 1999-11-30 | Promotion or inhibition of angiogenesis and cardiovascularization |
PCT/US1999/028551 WO2000053750A1 (en) | 1999-03-08 | 1999-12-02 | Compositions and methods for the treatment of tumors |
USPCT/US99/28564 | 1999-12-02 | ||
PCT/US1999/028564 WO2000055319A1 (en) | 1999-03-12 | 1999-12-02 | Methods and compositions for inhibiting neoplastic cell growth |
USPCT/US99/28551 | 1999-12-02 | ||
PCT/US1999/031274 WO2000053752A2 (en) | 1999-03-08 | 1999-12-30 | Promotion or inhibition of angiogenesis and cardiovascularization |
PCT/US1999/031243 WO2000053751A1 (en) | 1999-03-08 | 1999-12-30 | Methods and compositions for inhibiting neoplastic cell growth |
USPCT/US99/31243 | 1999-12-30 | ||
USPCT/US99/31274 | 1999-12-30 |
Related Parent Applications (1)
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PCT/US2000/000219 Continuation-In-Part WO2000053753A2 (en) | 1994-09-08 | 2000-01-05 | Promotion or inhibition of angiogenesis and cardiovascularization |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US2000/003565 Continuation-In-Part WO2001053486A1 (en) | 1994-09-08 | 2000-02-11 | Compositions and methods for the treatment of tumor |
US10/119,480 Continuation US20040087769A1 (en) | 1998-09-10 | 2002-04-09 | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
Publications (1)
Publication Number | Publication Date |
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WO2000053754A1 true WO2000053754A1 (en) | 2000-09-14 |
Family
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Family Applications (1)
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PCT/US2000/000277 WO2000053754A1 (en) | 1997-03-31 | 2000-01-06 | Compositions and methods for the treatment of tumor |
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AU (1) | AU2224800A (en) |
WO (1) | WO2000053754A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US7547767B2 (en) | 2002-09-24 | 2009-06-16 | Centocor Ortho Biotech Inc. | Growth arrest specific gene 6 peptides, antibodies, compositions, methods and uses |
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